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12 BLOOD AND LYMPH VASCULAR SYSTEMS Multicellular animals require a mechanism the capillaries are of great physiological im¬ for dist...

12 BLOOD AND LYMPH VASCULAR SYSTEMS Multicellular animals require a mechanism the capillaries are of great physiological im¬ for distribution of oxygen, nutritive materials, portance because it is this part of the circula¬ hormones, and other signaling molecules to tion that carries out the primary function of the tissues, and for collecting from them car¬ the vascular system. bon dioxide and other metabolic waste prod¬ ucts to be transported to the excretory organs for elimination. In vertebrates, these essential ARTERIES functions are carried out by the blood vascular system which consists of a muscular pump, the Blood is carried from the heart to the capil¬ heart, and two systems of blood vessels. One of lary networks in the tissues by arteries. These these, the pulmonary circulation, carries blood constitute an extensive system of vessels begin¬ to and from the lungs; the other, the systemic ning with the aorta and pulmonary artery, circulation (peripheral circulation), distributes which emerge from the left and right ventricles blood to all the other tissues and organs of of the heart, respectively. As they course away the body. In both, the blood pumped from from the heart, these vessels branch repeat¬ the heart passes successively through arteries edly and, thus, give rise to large numbers of of diminishing diameter, to networks of mi¬ arteries of progressively diminishing caliber. nute capillaries, and then back to the heart The basic organization of the wall of all ar¬ through veins of increasing caliber. teries is similar in that three concentric layers At each beat, the heart ejects into two large can be distinguished: (1) an inner layer, the vessels, the pulmonary artery and the aorta, tunica intima, consisting of an endothelial tube about 80 ml of blood, resulting in an outflow whose squamous cells generally have their of about 6 L/min. The initial velocity of blood long axis oriented longitudinally; (2) an inter¬ flow is about 33 cm/s, but the rate gradually mediate layer, the tunica media, composed decreases as the total cross-sectional area of mainly of smooth muscle cells oriented cir¬ the vascular system is increased by the re¬ cumferentially; and (3) an outer coat, the tu¬ peated branching of the arteries. A further nica adventitia, made up of fibroblasts and asso¬ expansion of the cross-sectional area of the ciated collagen fibers oriented, for the most system occurs quite abruptly at the level of part, longitudinally (Fig. 12-1 and 12-2A). the capillaries, resulting in a decrease in rate of This outer layer gradually merges with the flow to about 0.3 cm/s. The extensive capillary loose connective tissue around the vessel. The networks of the body have a total surface area boundary between the tunica intima and tu¬ of 700 m2, available for exchange of metabo¬ nica media is marked by the internal elastic lites with the tissues. It is only in the capillaries lamina (elastica interna), which is especially well and small venules that the vessel walls are thin developed in arteries of medium caliber. Be¬ enough and permeable enough to permit dif¬ tween the tunica media and the tunica adven¬ fusion of substances to and from the sur¬ titia, a more delicate external elastic lamina (elas¬ rounding tissues. The larger vessels are con¬ tica externa) is also distinguishable in many cerned with distribution of blood to the arteries. capillaries. At any given moment, only about There is a continuous gradation in diameter 5% of the total blood volume is in the capillar¬ and in the character of the vessel wall, from ies and 95% is on its way to or from them. the largest arteries down to the capillaries, The structure and functional properties of but arteries are usually classified as (1) elastic 368  Adventitia External elastic lamina Tunica media Internal elastic lamina brane Ad External Endothelium Internal elastic lamina Figure 12-1. Schematic representation of the principal structural components of a medium-sized artery. (Redrawn after Williams and Warwick. 1980. In Gray’s Anatomy, 38th British ed. Philadelphia, W.B. Saunders Co. Figure 12-2. Drawings of the wall of a small artery, in cross section, showing the concentric arrangement of the tunica intima, media, and adventitia. (A) Stained with hematoxylin and eosin; (B) stained with orcein to reveal the elastic tissue component. 369 370 BLOOD AND LYMPH VASCULAR SYSTEMS Intima Figure 12-3. Section through the pos¬ terior wall of the human aorta. Elastic Media tissue is black, other components are essentially unstained (after von Ebner, V. 1902 in Kolliker, A., Handbuck der Gewebelehre, Vol. 3, Leipzig.) [Pub¬ lisher not available] Vein Adventitia Vein arteries (conducting arteries), (2) muscular arter¬ separated from the elastica interna by loose ies (distributing arteries) and arterioles, on the connective tissue containing a few fibroblasts, basis of their size, the predominant compo¬ occasional smooth muscle cells, and thin colla¬ nent of their tunica media, and their principal gen fibers. The endothelium provides a function. smooth lining layer for the vessel and a partially selective diffusion barrier between the blood and the outer tunics of the vessel wall. Its cells ELASTIC ARTERIES are polygonal in outline, 10-15 pm wide and 25-50 pan long, with their long axis oriented The large elastic arteries, such as the pulmo¬ longitudinally. Adjacent endothelial cells are nary and aorta, brachiocephalic, subclavian, attached by simple occludingjunctions and oc¬ common carotid, and common iliac have walls casional gap junctions. The cells contain all of containing many fenestrated layers of elastin the common organelles, usually located in the in their tunica media (Fig. 12-3). Their walls thicker region of cytoplasm around the cen¬ may be distinctly yellow in the fresh state due trally placed and flattened nucleus. The endo¬ to the abundance of elastin. These major con¬ thelium is a very slowly renewing population ducting vessels are distended during contrac¬ of cells that are rarely found in division. Their tion of the heart (systole), and the subsequent adluminal and abluminal membranes have elastic recoil of their walls during diastole numerous associated small vesicles that are serves as a subsidiary pump maintaining con¬ believed to be involved in transendothelial tinuous flow despite the intermittency of the transport of water, electrolytes, and certain heart beat. macromolecules. Short blunt processes occa¬ The tunica intima of these arteries consists sionally extend from the base of the endothelial of the endothelium, a thin squamous epithelium, cells through fenestrae in the elastica interna  BLOOD AND LYMPH VASCULAR SYSTEMS 371 and establish junctions with smooth muscle lae of elastin alternating with thin layers con¬ cells in the media. sisting of circularly oriented smooth muscle Rod-like cytoplasmic inclusions are ob¬ cells, and fibers of collagen and elastin in a served in electron micrographs of arterial en¬ proteoglycan extracellular matrix. The elastic dothelium. These are named Weibel-Palade lamellae and other extracellular components bodies after the cytologists who first described are apparently secreted by the smooth muscle them. They are membrane-bounded struc¬ cells. The elastica interna is less prominent tures about 0.1 nm in diameter and up to 3 than it is in muscular arteries. It is merely the /xm long and they contain tubular elements of innermost of the many elastic laminae in the unknown composition in a moderately dense wall. In the adult, these may number 50 or matrix. 7 hey are sites of storeage of von Wille- more in the thoracic aorta and about 30 in brand factor, a very large glycoprotein synthe¬ the abdominal aorta. The three-dimensional sized by endothelial cells throughout the vas¬ configuration of the elastic components of the cular system but stored in Weibel-Palade vessel wall are difficult to visualize in histologi¬ bodies only in arteries. This factor is believed cal sections, but it is possible to remove all to be secreted continuously into the blood other components with hot formic acid and plasma. It is a major participant in blood plate¬ to examine the unextracted elastin with the let aggregation and adhesion to form a clot at scanning electron microscope. In such prepa¬ sites of injury to the vessel wall. Its congenital rations, it is apparent that the elastic lamellae absence results in von Willebrand disease, char¬ have relatively large fenestrations of varying acterized by prolonged blood coagulation size and shape and the successive lamellae time and excessive bleeding after injury. are joined by slender interconnecting strands The tunica media of elastic arteries is made of elastin (Figs. 12-4 and f2-5). Owing to up of multiple concentric, fenestrated lamel¬ the abundance of elastin in the l^rge elastic Figure 12-4. Scanning electron micrograph of the three-dimensional architecture of the elastin in the wall of rat aorta extracted with hot formic acid to remove all other tissue components. The elastic tissue consists of multiple concentric sheets or laminae interconnected by radially oriented strands and fenestrated septa. In the intact aorta, smooth muscle cells occupied the spaces demarcated by these elastic elements. (Micrograph courtesy of Wasano, K. 1983. J. Electron Microsc. 33:32.) 372 BLOOD AND LYMPH VASCULAR SYSTEMS Figure 12-5. (A) Scanning micrograph showing a surface view of the aortic internal elastic lamina of the rat. It is characterized by large fenestrations traversed by an irregular meshwork of thin strands of elastin. (B) In contrast, the internal elastic lamina of the femoral artery shows relatively small round fenestrations. (Micrograph courtesy of Wasano, K. 1983. J. Electron Microsc. 32:33.) arteries, smooth muscle makes up a relatively of nutrients. Blood is returned via small veins small fraction of the media. In the aorta of that are confluent with nearby larger veins. the rabbit, smooth muscle constitutes only 35% of the volume of the wall, compared to 74% in the tibial artery, a distributing MUSCULAR OR artery. DISTRIBUTING ARTERIES The tunica adventitia of elastic arteries is relatively thin and consists of fibroblasts, lon¬ As the elastic arteries gradually diminish in gitudinal bundles of collagen fibers, and a diameter and in the thickness of their wall, loose network of thin elastic fibers. The walls they give off lateral branches with walls con¬ of the large elastic arteries are too thick to be taining less elastin and more smooth muscle. nourished by diffusion from the lumen of the These muscular or distributing arteries include vessel. Such arteries have a microvasculature the branchial, femoral, radial, and popliteal of their own. Small blood vessels called vasa arteries and their branches. This category in¬ vasorum ramify over the surface of the vessel to cludes the majority of vessels in the arterial form a network in the adventitia from which system, spanning a wide range of sizes down capillaries penetrate into the media. How far to 0.5 mm in diameter. inward they extend is debated, but it is likely The intima is thinner than that of the elastic that at least the outer half and possibly more arteries but otherwise similar in its organiza¬ of the wall receives nutrients and oxygen from tion. Peripheral to the intima, in cross sections, the vasa vasorum. This still leaves a consider¬ there is a conspicuous elastica interna which able thickness of the wall dependent on diffu¬ often has an undulating contour, owing to sion from the lumen. Fenestration of the elas¬ agonal contraction of the media of the vessel tic lamellae is thought to facilitate diffusion (Figs. 12-6 and 12-7). The endothelium  BLOOD AND LYMPH VASCULAR SYSTEMS 373 closely conforms to the undulations of the are much smaller than those in the walls of elastica interna and extends processes the hollow viscera. In laboratory rodents, the through its fenestrations to establish junctions vascular smooth muscle cells are about 40 p,m with the innermost smooth muscle cells of the in length in arterioles and 130 p,m in large media. The fenestrations in the elastica in¬ arteries, compared to 400-500 /nm in smooth terna are also believed to be essential for nutri¬ muscle cells in the wall of the intestine. tion of the avascular media, permitting diffu¬ The individual cells of the media are enve¬ sion of small molecules from the lumen. The loped by a typical basal lamina (Fig. 12-8). gapjunctions formed by the cell processes that Short processes extend through discontinu¬ traverse the fenestrae serve to maintain meta¬ ities in this layer to form gap junctions with bolic coupling of the endothelium to the neighboring cells. These low-resistance junc¬ smooth muscle of the media. tions are essential for coordination of muscle The thickness of the media varies from contraction throughout the tunica media. three or four layers of smooth muscle cells in With traditional silver-staining methods, the small arteries to as many as 40 in large arteries. cells were also seen to be surrounded by a The size and arrangement of the cells are best network of reticular fibers. In electron micro¬ observed in scanning electron micrographs of graphs, these are identified as bundles of thin vessels, after extraction of perivascular and collagen fibrils in the narrow intercellular intramural connective tissue. The myocytes spaces. The collagen fibrils of the media and are circumferentially oriented and closely those of the intima are of small diameter (30 packed in parallel array. A few slender bun¬ nm) and chondroitin sulfate is the predomi¬ dles of longitudinally oriented smooth muscle nant glycosaminoglycan of the surrounding cells may be found at the interface between matrix. The collagen fibrils of the adventitia the intima and media and between the media are distinctly larger (60-100 nm) and the asso¬ and adventitia. Vascular smooth muscle cells ciated matrix is rich in dermatan sulfate and Figure 12-6. Photomicrograph of a muscular artery from the rat stained with aldehyde fuchsin for elastin. The elastica interna, elastica externa, the media, and the thick adventitia are clearly shown. An area comparable to that enclosed in the larger rectangle is illustrated in an electron micrographs in Fig. 12-7.  Lumen dothelium Elastica interna Smooth muscrfe Figure 12-7. Transmission electron micrograph of a section through the wall of a small muscular artery (for orientation, see the rectangle in Fig. 12-6). The elastica interna has a wavy outline owing to agonal contraction of the vessel wall. It is traversed at intervals by small fenestrations through which processes of endothelial cells pass to contact smooth muscle cells in the tunica media. :* - -^*5= * Figure 12-8. Electron micrograph of a portion of the wall of a small artery in longitudinal section. The elastica interna is not stained and, therefore, appears as a clear area between the endothelium and the smooth muscle of the media. 374  BLOOD AND LYMPH VASCULAR SYSTEMS 375 heparan sulfate. The smaller fibrils in the me¬ cells (Fig. 12-2B). In electron micrographs, dia are a product of the smooth muscle cells they are recognizable as irregular linear pro¬ whereas the larger ones, in the adventitia, are files that are unstained by osmium or the ura- formed by fibroblasts. It is not clear whether nyl acetate commonly used. this difference in fiber diameter is directly re¬ In histological sections, the elastica externa lated to the cell of origin or whether the chon- often appears as a continuous lamina at the droitin sulfate glycosaminoglycan in the extra¬ junction of the media and adventitia (Fig. 12- cellular matrix of the media limits fiber 9), but in electron micrographs, it is a discon¬ diameter by influencing collagen assembly. tinuous layer of elastin, considerably thinner The media also contains slender elastic fi¬ than the elastica interna. Closely applied to its bers with a prevailing circumferential orienta¬ outer surface are occasional small fascicles of tion. In preparations stained with aldhyde- unmyelinated nerve axons, some containing fuchsin or resorcin-fuchsin, they appear as local accumulations of mitochondria and nu¬ dark wavy lines among the smooth muscle merous synaptic vesicles (Fig. 12-10). The Innominate Airtery Thoracic Aorta Arch of Aorta Anterior Cerebral Artery Radial Artery Femoral Artery Figure 12-9. Photomicrographs of the wall of elastic and muscular arteries of a macaque, illustrating variations in relative thickness and the differing amounts and distribution of the elastic tissue, which has been stained with resorcin-fuchsin. (From Cowdry, E.V. 1950. Textbook of Histology. Philadelphia, Lea and Febiger.) 376 BLOOD AND LYMPH VASCULAR SYSTEMS Figure 12-10. Electron micrograph of the junctional zone between the media and adventitia of a small muscular artery. (For orientation, see lower box in Fig. 12-6). The media is limited, on its outer aspect, by a discontinuous elastica externa. Closely applied to this are small nerves, some of whose axons contain numerous synaptic vesicles. nerves do not penetrate into the media but to classify vessels in the transitional region. appear to terminate at the elastica externa. Some arteries of intermediate caliber (e.g., The neural stimulation of the smooth muscle popliteal and tibial arteries) have walls that cells evidently depends on diffusion of the resemble those of larger arteries, whereas neurotransmitter through fenestrations in some large arteries (e.g., external iliac) have this layer of elastin. The resulting depolariza¬ walls not unlike those of medium-sized arter¬ tion of the peripheral smooth muscle cells is ies. The transitional regions between elastic propagated throughout the media via the gap and muscular arteries are often designated junctions between cells. arteries of mixed type. Examples are the external The tunica adventitia of muscular arteries carotid, axillary, and common iliac arteries. may be thicker than the media (Figs. 12—2, Their walls contain islands of smooth muscle 12-6). It consists of fibroblasts, elastic and col¬ in the tunica media that either separate the lagen fibers, oriented, for the most part, longi¬ elastic laminae or interrupt their continuity. tudinally. These grade into the surrounding The visceral arteries that arise from the ab¬ connective tissue without a clearly defined dominal aorta are also of mixed type. In the boundary. The loose organization and pre¬ transitional region, the tunica media may con¬ vailing longitudinal orientation of its compo¬ sist of two distinct zones—an inner muscular nents imposes little restraint on changes in zone and an outer zone of elastic laminae. diameter of the vessel in vasoconstriction The thickness of the tunica media of arter¬ and vasodilatation. ies varies according to the internal pressure to which it is subjected. The coronary arteries of the heart are subjected to relatively high TRANSITIONAL AND internal pressure and have a wall that is SPECIALIZED ARTERIES thicker than that of other muscular arteries of comparable size. Similarly, in the arteries In the gradual structural changes from one of the lower limbs, the media is thicker than type of artery to another, it is often difficult in corresponding arteries of the upper limbs.  BLOOD AND LYMPH VASCULAR SYSTEMS 377 Blood pressure in the pulmonary circulation tion because they constitute the principal is considerably lower than in the systemic cir¬ component of the peripheral resistance to culation. Accordingly, the blood vessels in the flow that regulates the blood pressure. Arte¬ lung are relatively thin-walled. A unique fea¬ rioles range in diameter from 200 /rm down ture of the pulmonary circulation is the pres¬ to about 40 |xm. Their tunica intima consists ence of cardiac muscle extending from the of a continuous endothelium and a very thin heart, for a short distance, into the initial por¬ subendothelial layer consisting of reticular tion of the large pulmonary artery. and elastic fibers. A very thin and fenestrated Within the cranial cavity, where vessels are elastica interna is present in the larger arteri¬ protected from external pressure and tension, oles but absent in terminal arterioles. In the the dural and cerebral arteries have relatively larger arterioles, the tunica media.consists thin walls. The elastica interna is well devel¬ of two layers of smooth muscle cells, but in oped but the tunica media is thin and virtually the smallest arterioles, there is a single layer devoid of elastic fibers (Fig. 12-9). and the individual cells completely encircle In other sites, where vessels are subject to the endothelium (Figs. 12-11, 12-12, and frequent bending and traction, as in the popli¬ 12-13). Collagen fibers and occasional fi¬ teal artery behind the knee joint and in the broblasts form a very thin tunica adventitia. axillary artery in the axilla, longitudinal bun¬ In the vessels of the short transitional region dles of smooth muscle are more prevalent in between arterioles and capillaries, sometimes the tunica intima than they are in comparable called metarterioles, smooth muscle does not vessels elsewhere in the body. form a continuous layer, but individual smooth muscle cells, completely encircling the endothelial tube, are spaced a short dis¬ ARTERIOLES tance apart. Their contraction is believed to give this region a sphincter-like function, The small arteries and arterioles are a physi¬ controlling the inflow of blood into the capil¬ ologically important segment of the circula¬ lary bed. Figure 12-11. Scanning electron micrograph of a branching arteriole showing the circumferential arrangement of the single layer of smooth muscle cells. (Micrograph courtesy of J. Desaki and Y. Uehara.) 378 BLOOD AND LYMPH VASCULAR SYSTEMS for shunting arterial blood directly into the venous system. When they are contracted, all of the blood passes through the network of capillaries; when they are relaxed, opening their lumen, a considerable volume of blood passes directly into the veins. Arteriovenous anastomoses, therefore, play an important role in regulating blood flow to the region. This regulatory function is perhaps best ex¬ emplified in the skin where arteriovenous anastomoses are an important component of the physiological mechanism for thermoregu¬ lation. When they are open, blood at deep body temperature can flow through the hypo- dermal venous plexus at an increased rate, resulting in a much greater loss of heat to the environment. In various mammalian species, the number and distribution of cutaneous ar¬ teriovenous anastomoses is adapted to their special requirements for thermoregulation. For example, in sheep in which the insulating fleece limits evaporative heat loss from much of the body surface, the bare nose, ears, and lower legs are of greatest importance in heat regulation. The number of arteriovenous anastomoses per square centimeter of skin on the lower leg (72) is about five times the num¬ Figure 12-12. Scanning micrograph of the wall of a suba¬ rachnoid muscular arteriole, showing the closely apposed, ber on the trunk (15). Even more impressive circumferentially oriented smooth muscle cells. (Micro¬ examples are to be found in seals and other graph from Uehara, Y. T. Fujiwara, and K. Kaidoh. 1990. In aquatic mammals continuously exposed to D.M. Motta, ed. Ultrastructure of Smooth Muscle. Boston, arctic seawater. In addition to an external in¬ Kluwer Academic Publishers.) sulation of thick fur, they have a subcutaneous insulating layer of blubber to minimize heat loss. But on land, excess heat is dissipated ARTERIOVENOUS ANASTOMOSES through the fore and hind flippers which lack this insulation. The arteriovenous anastomo¬ In many parts of the body, the terminal ses in the skin of the flippers number up to ramifications of arteries are connected to the 1200 per square centimeter compared to veins not only through an intervening net¬ about 100 in the skin of the trunk. Compara¬ work of capillaries, but also by direct arteriove¬ ble studies of the AVAs of human skin have nous anastomoses (AVA) of larger caliber. not been made. They are much less numerous These arise as side branches of small arteries than in the above species and the regional and directly join small veins. Three morpho¬ differences in their abundance are less logically distinct segments are recognizable marked. along their course. The initial segment is simi¬ Arteriovenous anastomoses are richly in¬ lar in structure to the small artery of which it nervated with both adrenergic and choliner¬ is a branch. The terminal segment resembles gic periadventitial nerves. The nerves are the small vein with which it is confluent. Be¬ most abundant around the thick intermediate tween these is a contractile intermediate seg¬ segment with the majority being adrenergic. ment with a wall that is unusually thick for a The contractions of arteriovenous anastomo¬ vessel of this size. In addition to a media, it ses are described as being rapid, forceful, and has a subendothelial layer of plump cells that relatively independent of the vasomotor activ¬ are polygonal in cross sections viewed with ity of neighboring arteries. There is evidence the light microscope. These were traditionally that they are under control of the thermoreg¬ described as “epithelioid,” but ultrastructural ulatory centers in the brain, whereas other studies have now shown that they are longitu¬ peripheral arteries are more responsive to lo¬ dinally oriented modified smooth muscle cells. cally generated stimuli. Arteriovenous anastomoses provide a path In addition to these relatively simple shunts  BLOOD AND LYMPH VASCULAR SYSTEMS 379 Figure 12-13. Electron micrograph of a typical small arteriole with a single layer of smooth muscle cells around the endothelium. between small arteries and veins, there are flow of blood through the capillaries would more complex communications through small be intermittent, but, in fact, it is continuous. organs called glomera located mainly in the Because the wall of the large elastic arteries nailbeds, the pads of the fingers and toes, and is distensible, only a portion of the force gen¬ in the ears. An afferent arteriole traverses the erated by contraction of the heart is dissipated connective tissue capsule of the glomus, loses in advancing the column of blood in their lu¬ its internal elastic lamina, and acquires a sube- men. The rest of the force goes to expanding ndothelial layer of epithelioid smooth muscle the walls of the large arteries. The potential cells. The vessel may branch or become highly energy accumulated in the stretching of their convoluted within the glomus before continu¬ walls during contraction of the heart (systole) ing as a short, thin-walled vein that emerges is dissipated in the elastic recoil of their walls from the glomus and joins the hypodermal during relaxation of the heart (diastole). The venous plexus. The glomera are very richly release of tension in the wall of the elastic innervated. They seem to be far more com¬ arteries serves as an auxiliary pump, forcing plex than is required for simple shunting of the blood onward during diastole when no blood from arteries to veins and are suspected force is being exerted by the heart. Thus, al¬ by some investigators to have an additional though the flow is pulsatile throughout the function that is yet to be discovered. initial portion of the system, the elasticity of the wall of the large arteries ensures a continu¬ ous flow through the capillaries. PHYSIOLOGICAL IMPLICATIONS OF A vasomotor center in the brain continuously THE STRUCTURE OF ARTERIES generates impulses that travel via nerves in the spinal cord to the sympathetic chain, and The intermittent contraction of the heart then over vasomotor nerves to all of the blood results in a pulsatile flow of blood in the large vessels except the capillaries. As a result of arteries. If the walls of the arteries were rigid, these impulses, the smooth muscle in the me- 380 BLOOD AND LYMPH VASCULAR SYSTEMS dia of the distributing arteries is maintained sel, one can observe the striking differences in a state of partial contraction referred to as in the caliber of the lumen and in the charac¬ vasomotor tone. The nerves to the blood vessels ter of the vessel wall, that are associated with include both vasoconstrictor and vasodilator fi¬ vasoconstriction (Fig. 12—14). Because the ar¬ bers, permitting modulation of the caliber of teries provide the principal resistance to flow the vessels to change the pressure in the sys¬ in the system, a generalized vasoconstriction tem as a whole or to increase or decrease blood results in a marked increase in the blood flow to particular areas. pressure. In histological sections, the smooth muscle Smooth muscle cells of the arteries have re¬ of the majority of the arteries has undergone ceptors for a number of humoral agents other some degree of contraction after death or in than the sympathetic neurotransmitter nor¬ response to immersion in a chemical fixative. epinephrine. A fall in blood pressure causes One, therefore, gets an erroneous impression the kidneys to secrete renin, an acid protease of the thickness of the arterial wall in relation that cleaves angiotensinogen in the circulating to the diameter of the lumen. The remarkable blood, to yield angiotensin, a potent vasocon¬ capacity of arteries to change their caliber is strictor. The resulting generalized vasocon¬ best observed in the living, anaesthetized ani¬ striction raises the blood pressure. A fall in mal. If a droplet of the neurotransmitter, nor¬ blood pressure, associated with severe hemor¬ epinephrine, is applied to an artery, the under¬ rhage, also causes the posterior lobe of the lying portion of the vessel will undergo a pituitary gland to release a peptide hormone, marked local vasoconstriction. The vessel can vasopressin, which is another very potent vaso¬ then be rapidly fixed in situ and prepared constrictor. for histological study. In sections through the Local constriction of arteries may also be open and the constricted segments of the ves¬ induced by products of tissue injury, an effect Adventitia Media Intima Elastica interna Media 25u Figure 12-14. Low-power electron micrographs of two cross sections less than 1 mm apart in the same frog arteriole. A microdroplet of norepinephrin was applied to the living vessel, causing local vasoconstriction in the area indicated by brackets (inset). The vessel was then fixed, in situ, and sectioned. These two sections provide a dramatic demonstration of the structural correlates of vasoconstriction. (From Phelps, P.C. and J.H. Luft. 1969. Am. J. Anat. 125:3999.)  BLOOD AND LYMPH VASCULAR SYSTEMS 381 that is important in limiting blood loss. There often stacked in parallel array. The most dis¬ are other local factors acting at the level of tinctive feature of these cells is the presence small arteries and arterioles that influence in their cytoplasm of dense-cored vesicles (60- blood flow. If flow is briefly interrupted, oxy¬ 200 nm) which resemble those in cells of the gen deprivation and accumulation of carbon adrenal medulla. The cell processes contain dioxide and lactic acid in the tissues cause re¬ longitudinally oriented microtubules, a few laxation of smooth muscle in the walls of these dense-cored vesicles and numerous small vesi¬ small vessels so that when circulation is re¬ cles with an electron-lucent interior. In some stored the rate of flow may be two to six times species, two categories of glomus cells (types greater than it was before. This reactive hyper- A and B) are distinguishable on the basis of aemia, tending to correct a local deficit of me¬ the size and number of their dense-cored vesi¬ tabolites, is independent of the nervous cles. In type A, these are about 30% larger system. and twice as numerous as those in type B. Nerve endings are closely associated with type-A cells, but are seldom seen in contact SENSORY ORGANS OF ARTERIES with cells of type B. Sheath cells have a more complex three-di¬ Sensory nerves are associated with arteries mensional configuration, including long ta¬ throughout the vascular system, but at certain pering or lamelliform processes that envelope sites, there are specialized neural organs from two to six glomus cells, covering nearly whose function is to monitor the pressure and all of their surfaces, that are not in contact composition of the blood. Chief among these with nerve endings or other glomus cells. The are the carotid bodies, aortic bodies, and carotid nuclei of the sheath cells are more irregular sinus. These sensory organs are of great im¬ in shape and contain more heterochromatin portance in regulating respiration, heart beat, than those of the glomus cells. Their cyto¬ and the vasomotor activities controlling blood plasm contains no dense-cored vesicles. pressure. Sheath cells are quite similar to sustentacular The carotid bodies are inconspicuous organs cells in other sensory organs and to the glial about 3 mm wide and 5 mm long located in cells of the nervous system. Where nerves en¬ the connective tissue associated with the vessel ter groups of glomus cells they lose their in¬ walls at the bifurcation of the common carotid vestment of Schwann cells and their terminal artery to form the external and internal ca¬ portion is surrounded by sheath cells. These rotid arteries. They are richly innervated, cells do not form a complete diffusion barrier have a large blood flow in relation to their around the glomus cells because when probes size, and contain chemoreceptors responsive to such as horseradish peroxidase are injected changes in the oxygen, carbon-dioxide, and intravascularly, they permeate the intercellu¬ hydrogen ion concentrations of the blood. Af¬ lar clefts throughout the carotid body. ferent nerves from these organs transmit sig¬ Certain cells of the carotid body exhibit a nals to a respiratory center in the brain that con¬ brown color of the cytoplasm when exposed trols respiration. to a solution of potassium dichromate. This The carotid body consists of multiple clus¬ staining, referred to as the chromaffin reaction, ters of pale-staining cells embedded in a is believed to detect the presence of catechola¬ highly vascular connective tissue stroma. The mines. It is characteristic of the cells of the parenchymal cells are of two types identifiable adrenal medulla and of paraganglia, small with the light microscope on the basis of their clusters of epithelioid cells that are widely scat¬ nuclear form and staining properties. They tered in the retroperitoneal tissues. Owing to are more easily distinguished in electron mi¬ its chromaffinity, the carotid body was in¬ crographs. The glomus cells (type-I cells) usually cluded in the system of paraganglia. This has appear round or oval in section but they may been questioned by some histologists who have a few processes of varying length that found marked species differences in the chro¬ contact other glomus cells or capillaries. They maffinity of the glomus cells and a variable, occur in clusters that are surrounded by sheath and marginal, reaction among cells in the cells (type-II cells). same glomus. However, it is now widely ac¬ The glomus cells have a large nucleus, a cepted that cells of the carotid body exhibit prominent juxtanuclear Golgi complex, nu¬ some degree of chromaffinity and that they merous mitochondria, and ribosome-studded contain catecholamines demonstrable by cisternae of endoplasmic reticulum that are other histochemical procedures. Whether 382 BLOOD AND LYMPH VASCULAR SYSTEMS some of the cells also contain peptide hor¬ serves as a baroreceptor reacting to changes in mones remains unsettled, but the presence of blood pressure and initiating afferent im¬ two size categories of dense-cored vesicles in pulses that trigger appropriate vasomotor ad¬ their cytoplasm suggests this possibility. justments to maintain a pressure within nor¬ The carotid bodies are richly innervated by mal limits. A few baroreceptors are also branches of the glossopharyngeal nerve that present in the wall of the aorta and other large are made up of axons whose cell bodies are arteries in the thorax and neck, but these are located in the petrosal ganglion. The axon not visually identifiable. terminals associated with the glomus cells are quite pleomorphic, some being calyceal and others simple boutons. An enduring contro¬ CHANGES IN ARTERIES WITH AGE versy as to whether these nerves are afferent (conducting toward the brain) or efferent The walls of large arteries undergo a grad¬ (conducting away from the brain) has been ual process of further growth and develop¬ resolved in favor of the view that they are ment from birth to age 25. In elastic arteries, afferent sensory nerves. In the great majority there is a progressive thickening of the wall of the synapses, the glomus cells are presynap- and development of increasing numbers of tic. Aggregations of dense-cores vesicles and elastic laminae. In muscular arteries, the of small lucent-cored vesicles are found in the thickness of the tunica media increases with cell body near the synaptic cleft, whereas rela¬ little or no addition of elastin. From middle tively few vesicles are found in the axoplasm age onward, there is a relative increase in col¬ of the nerve ending. In the great majority of lagen and proteoglycans and the walls of the synapses, the glomus cell is presynaptic, but, larger arteries consequently become less pli¬ rarely, two synapses may be found in close ant. More significant age-related changes are proximity with the aggregation of vesicles in found in the intima. Extracellular matrix com¬ one, being presynaptic, and in the other, post- ponents slowly accumulate and intimal synaptic, thus constituting a reciprocal synapse. smooth muscle cells become more numerous. The significance of these is unclear. The late stages of development of the arte¬ The localization of the chemoreceptor func¬ rial wall cannot be clearly differentiated from tion of the carotid body has not been definitely the early regressive changes associated with established, but it is assumed that it resides in aging and the onset of arteriosclerosis (“harden¬ the glomus cells and that these release signals ing of the arteries”). Arteries are constantly carried over afferent sensory neurons. An al¬ subjected to mechanical stresses due to the ternative interpretation postulates that the re¬ oscillations of intralumenal pressure associ¬ ceptor function is in the nerve endings, with ated with intermittent contractions of the the glomus cells acting as interneurons modu¬ heart and they seem to be more susceptible to lating the chemoreceptive sensitivity of the wear-and-tear than other tissues. The larger nerve endings. arteries, particularly the aorta, iliac, femoral, Other chemoreceptor organs, the aortic bod¬ coronary, and cerebral arteries, are especially ies, are situated on the arch of the aorta be¬ prone to develop atherosclerosis, a disease that tween the origins of the subclavian and com¬ is the principal basis of heart attack (myocardial mon carotid arteries on the right, and medial infarction) and stroke (cerebral thrombosis). to the origin of the subclavian on the left. The Atherosclerosis is characterized by patchy structure and function of these bodies appear thickenings of the intima that contain intracel¬ to be identical to those of the carotid bodies. lular and extracellular deposits of lipid. By In the internal carotid artery immediately the age of 15, small focal accumulations of above the bifurcation of the common carotid, lipid-laden smooth muscle cells, surrounded there is a slight dilatation called the carotid by deposits of cholesterol-rich lipid, form yel¬ sinus. In this local specialization of the vessel low “fatty streaks” visible to the naked eye wall, the tunica media is thinner than else¬ in the intima of the aorta. These gradually where, whereas the adventitia is thicker and increase until they occupy 30% or more of contains numerous sensory nerve endings of the intimal surface by the age of 25. Whether the carotid sinus branch of the glossopharyn¬ these early-appearing fatty streaks are physio¬ geal nerve. The thinning of the media makes logical or are precursors of the more advanced this region of the vessel wall more distensible. lesions of atherosclerosis is debated. More pat¬ The nerve endings in the adventitia are stimu¬ ently pathological are the fibrous plaques that lated by stretch. The carotid sinus, therefore, appear in older individuals. These are white  BLOOD AND LYMPH VASCULAR SYSTEMS 383 in color and thicker, so that they project nal lamina that is continuous with the basal slightly into the lumen. These arise by local lamina of the endothelium, except at focal proliferation of the smooth muscle cells of the gap junctions between their processes and the intima and by migration of smooth muscle underlying endothelial cells. Pericytes have cells of the tunica media through fenestrations the usual complement of cytoplasmic organ¬ in the internal elastic lamina to join those in elles, including a small Golgi complex, mito¬ the intima. Normally, smooth muscle cells of chondria, and a few meandering tubules and the arterial wall are a very slowly renewing cisternae of the endoplasmic reticulum. Lyso- population, but where there is damage to the somes are common in the pericytes of brain endothelium and aggregation of blood plate¬ capillaries but are relatively few in the peri¬ lets, as there is in the earliest stages of athero¬ cytes of capillaries elsewhere. Microtubules, sclerosis, there is a local release of platelet-de¬ originating at the centrosome, extend along rived growth factor (PDGF), which stimulates the axis of the primary cell processes, and proliferation of smooth muscle cells. Lipid ac¬ bundles of filaments in the peripheral cyto¬ cumulates in and around these cells and they plasm terminate in densities on the inner as¬ are stimulated to produce more collagen and pect of the plasma membrane. proteoglycans that contribute to the local It has long been speculated that the peri¬ thickening of the tunica intima. As the disease cytes might be contractile. This has now been progresses, there is cell necrosis, erosion of verified by the demonstration that pericytes, the endothelium, and aggregation of blood in large capillaries and postcapillary venules, platelets to form a mural thrombus (blood contain tropomyosin, isomyosin of the smooth clot) that may occlude the lumen. muscle type, and a protein kinase that is in¬ The principal processes involved in arterio¬ volved in the control of contraction in muscle. sclerosis, thus, seem to be local proliferation Thus, pericytes appear to be contractile cells of smooth muscle cells, their production of involved in the control of blood flow through excess extracellular matrix, and the intracellu¬ the microvasculature. There is suggestive evi¬ lar and extracellular accumulation of lipid. dence that, in the revascularization following Research on the pathogenesis of the disease is tissue injury, pericytes may undergo further now concentrating on the role of cholesterol, differentiation to become smooth muscle cells various plasma lipoproteins, and mitogens re¬ in the walls of arterioles and venules. leased at the site by activated blood platelets. The caliber of the capillaries in different regions of the body varies within relatively narrow limits, averaging from 9 to 12 Aim in CAPILLARIES diameter, which is just large enough to permit unimpeded passage of the cellular elements The terminal branches of the arterioles of the blood. In organs that are in a state have a short transitional region in which occa¬ of minimal functional activity, many of the sional smooth muscle cells persist around the capillaries are narrowed so that little or no endothelial tube. Where these adventitial cells blood circulates through them. Normally, end, the vessels continue as small, thin-walled, only about 25% of the total capillary bed of endothelium-lined tubes of uniform diameter the body is patent, but with increased physio¬ that branch and anastomose frequently to logical activity, the narrowed vessels open, and form extensive capillary networks in the tis¬ flow through them is restored to meet an in¬ sues throughout the body (Figs. 12-15 and creased need for exchange of metabolites. 12-16). The capillary wall consists of ex¬ In cross sections of small capillaries, the lu¬ tremely attenuated endothelial cells, with men may be encircled by a single endothelial their basal lamina supported by a sparse net¬ cell (Fig. 12-19). In larger capillaries, the wall work of reticular fibers. Scattered along the may be made up of portions of two or three outside of the capillaries are cells called peri¬ cells. The cell nucleus is greatly flattened and, cytes. Unlike the fusiform, circumferentially thus, appears elliptical in section. The thicker oriented smooth muscle cells associated with nuclear region of the cell bulges into the lu¬ arterioles, the pericytes usually have long pri¬ men, whereas the attenuated peripheral por¬ mary processes deployed longitudinally along tion of the cell is extremely thin, with the adlu- the capillary wall and secondary processes ex¬ menal and ablumenal membranes separated tending from the primary processes, circum¬ by a layer of cytoplasm 0.2 to 0.4 Aim thick. ferentially around the vessel (Figs. 12-17 and A small Golgi complex and a few mitochon¬ 12—18). Pericytes are enclosed in a thin exter¬ dria are found in the juxtanuclear cytoplasm. 384 BLOOD AND LYMPH VASCULAR SYSTEMS Figure 12-15. Photomicrograph of normal human retinal blood vessels. These were isolated by tryptic digestion of the neural and receptor elements, leaving behind only the vessels. At the left is an arteriole, and at the right, a venule; between them is a network of capillaries of very uniform caliber. (Photomicrograph courtesy of T. Kuwabara.) Tubular elements of the endoplasmic reticu¬ three narrow sites of closer membrane approx¬ lum extend into the thinner peripheral por¬ imation can be detected (Fig. 12-22). At these tions of the cell. A conspicuous feature of en¬ sites, in freeze—fracture preparations, one dothelial cells is the presence of a large finds, on the E-face, parallel intramembranous number of vesicles associated with the plas- strands comparable to those occurring in the malemma at both surfaces of the cell (Figs. zonulae occludentes of other epithelia. 12-20, 12-24). At the resolution afforded by the light mi¬ Although endothelial cells are similar in ap¬ croscope, capillaries, in most tissues and or¬ pearance throughout most of the vascular sys¬ gans, appear quite similar, but with the elec¬ tem, they have been shown to have regional tron microscope, two distinct types can be differences in the types of intermediate fila¬ distinguished (Figs. 12-23 and 12-24). In ments that make up their cytoskeleton. Some muscle, nervous tissue, and the connective tis¬ contain desmin filaments only, others vimen- sues, the endothelium forms an uninter¬ tin filaments only, and still others have both. rupted layer around the lumen of the capil¬ Whether these variations reflect different lary. Such vessels are designated continuous functional properties or different embryolog- capillaries (or muscle-type capillaries). In the ical origins of the cells is not clear. The lume- pancreas, intestinal tract, kidney cortex, and nal surface of the endothelium is generally endocrine glands, the peripheral portions of smooth contoured, but the thin margins of the endothelial cells are interrupted by circu¬ the adjacent cells may overlap slightly and a lar fenestrations or pores, 60-70 nm in diame¬ thin marginal ridge, or flap, may project a ter, each closed by a very thin pore diaphragm short distance into the lumen (Fig. 12-21). (Figs. 12—24B and 12—25). When examined Zonulae adherentes and desmosomes are not in tissues that have been prepared by quick found between adjoining cells, but two or freezing, deep-etching, and replication by  BLOOD AND LYMPH VASCULAR SYSTEMS 385 Figure 12-16. Scanning electron micrograph of a corrosion cast of a typical capillary network from the submucosa of the hamster forestomach. (Micrograph from Imada, M., H. Tatsumi, and H. Fujita. 1987. Cell Tissue Res. 250:287.) platinum-carbon shadowing, the structure of nestrated capillaries of the body, those of the the diaphragm is more clearly revealed. It is renal glomerulus appear to be exceptional in made up of about eight fibrils that radiate, that the pores do not have pore diaphragms like spokes, from a central meshwork. The and their basal lamina is as much as three geometry of these fibrils create wedge-shaped times thicker than that of other capillaries. channels with their bases at the periphery of This may account for the fact that fluid tra¬ the pore. The maximum width of the broad verses the wall of glomerular capillaries as end of each wedge-shaped opening is about much as 100 times more rapidly than in mus¬ 5.5 nm. The dimensions of these channels are, cle capillaries. therefore, consistent with physiological stud¬ ies showing that the particulate tracer, horse¬ TRANSENDOTHELIAL EXCHANGE radish peroxidase (4.5 nm in diameter) readily escapes from such capillaries, whereas ferritin Physiologists have long speculated about (11 nm in diameter) does not. In such fenes¬ the mechanism of exchange across the capil¬ trated capillaries (visceral capillaries), seen in lary wall. The observed rates of passage of surface view under the scanning microscope water-soluble molecules could be accounted or in freeze—fracture preparations, the pores for by postulating two fluid-filled systems of are very uniformly distributed with a center- pores traversing the endothelium: one of to-center spacing of about 130 nm (Fig. 12— “small pores” about 9 nm in diameter and of 25). However, the areas exhibiting pores make relatively high frequency, and the other of up only a fraction of the vessel wall, with the “large pores” up to 70 nm in diameter and of remainder resembling the uninterrupted en¬ lower frequency. These pores were not seen dothelium of muscle capillaries. In the re¬ in electron micrographs of muscle capillaries sulting mosaic, the relative proportions of fe¬ and the structural equivalent of the postulated nestrated and unfenestrated areas vary in two sets of pores was a subject of lively debate. capillaries of different organs. Among the fe¬ To clarify this issue, electron-dense molecules 386 BLOOD AND LYMPH VASCULAR SYSTEMS sections have revealed that transient transen- dothelial channels may be formed by fusion of several vesicles, or in extremely thin areas, a single vesicle may open at both surfaces of the cell Fig. 12-26). Because the capillaries are the principal site of exchange of substances between the blood plasma and the tissue fluid, it is not surprising that there are more vesicles in capillary endothelium (~ 1000//ttm2) than in the endothelium of arterioles (~190//u,m2) or postcapillary venules (~645//zm2). Albumin is largely responsible for the col¬ loid osmotic pressure of the blood plasma and interstitial fluid and there is abundant physio¬ logical evidence for continuous movement of albumin from blood to the extra-vascular fluid. In addition to its oncotic properties, al¬ bumin serves as an important carrier of vari¬ ous kinds of molecules including fatty acids, steroid hormones, and thyroid hormone from the blood to their target tissues. Electron mi¬ crographs of capillaries perfused with gold- labeled albumin and fixed within 3 min reveal the dense gold particles selectively bound to the membranes of pits and vesicles open on Figure 12-17. Photomicrograph of an intact capillary in a the lumenal surface of the endothelium. After whole-mount of rat mesentery. The nuclei of the flattened 5 min, the vesicles carrying the tracer are lo¬ endothelial cells lining the capillary can be distinguished cated on the ablumenal side of the endothe¬ from those of the pericytes, which bulge outward from the lium discharging their contents into the extra- wall. vascular space. The endothelium of continuous capillaries in lung, heart, dia¬ phragm, and various other organs evidently of known dimensions greater than 10 nm have has albumin-receptors in its membrane that been introduced into the circulation and their aggregate in uncoated pits and vesicles that fate followed in electron micrographs. In provide a mechanism for selective transport muscle capillaries, these particles are rapidly of albumin and any molecules bound to it. taken up in vesicles opening onto the adlume- The process of transcytosis was originally nal surface of the continuous endothelium, envisioned as involving continuous formation then ferried across the cytoplasm, and dis¬ of vesicles at the adlumenal plasmalemma, charged into the extravascular space by fusion their detachment and movement across the of the vesicles with the ablumenal plas- cytoplasm, and fusion with the opposite mem¬ malemma (Fig. 12-26). brane. To account for the measured rate of The uptake of materials in small vesicles is albumin clearance, there would have to be a a form of endocytosis common to many cell continuous massive translocation of mem¬ types and is generally referred to as micropmo- brane from the lumenal to the ablumenal sur- cytosis. In cells other than endothelium, the face of the endothelium. Recent evidence sug¬ micropinocytosis vesicles moving into the cy¬ gests that, instead, the transport vesicles are toplasm from the plasmalemma usually fuse not all newly formed at the expense of the with lysosomes or become incorporated in plasma membrane but may be a separate and multivesicular bodies. The use of vesicles to relatively stable population arising from the ferry fluid and solutes across the cell is largely Golgi complex and simply shuttling back and confined to endothelial cells and is an expres¬ forth, undergoing alternate fusion and fission sion of their specialization for transport. The without intermixing of membrane constit¬ term transcytosis has been suggested to distin¬ uents at the plasmalemma (Fig. 12-26B). This guish this process from pinocytosis. In addi¬ model would be consistent with the images tion to the translocation of vesicles from one observed in electron micrographs and would surface of the endothelium to the other, serial not involve translocation of very large  BLOOD AND LYMPH VASCULAR SYSTEMS 387 T/IfD1"6-1? 1{!’ Scannin9 micrographs of small blood vessels showing pericyte processes encircling the vessel wall. (A) Pericyte of a capillary with primary processes directed longitudinally and secondary processes deployed circumferen¬ tially (B) Capillary with numerous associated pericytes. (C) Terminal arteriole showing a mixture of pericytes and circular smooth muscle cells. (Micrographs from Fujinara, T., and Y. Uehara. Amer. J. Anat. 170:39, 1984.) amounts of the plasmalemma from one side taken up mainly by adsorptive endocytosis in of the cell to the other. clathrin coated vesicles, whereas anionic or There is general agreement that the vesicles neutral tracers are shuttled across the endo¬ in muscle capillaries and the pores of fenes¬ thelium in noncoated transport vesicles. trated capillaries are the structural equivalents of the “large pores” postulated by physiolo¬ gists, but there is still disagreement as to the SPECIALIZED CAPILLARIES location of the “small pores” permitting pas¬ sage of molecules smaller than 9 nm. It is possi¬ Capillaries with the same morphological ap¬ ble that molecules of this size may pass through pearance may exhibit marked differences in discontinuities in the intercellular junctions. their permeability properties. Some 70 years Transendothelial transport is influenced by ago it was observed that intravenously injected factors other than molecular size, namely, by dyes that readily escape from the capillaries the chemical nature of the molecules, their of most tissues are retained in brain capillar¬ net charge, and the charge in the pathways ies. This gave rise to the concept of a special involved. In general, the surface of the endo¬ blood-brain barrier. Its structural basis re¬ thelium is negatively charged. When tracers mained conjectural until these capillaries of opposite charge, such as cationized ferritin, could be studied with the electron microscope. are perfused, they bind randomly on the plas¬ Their endothelial lining was found to be con¬ malemma and tenaciously to the diaphragms tinuous and devoid of fenestrations, transen¬ of fenestrated capillaries, but not to the vesi¬ dothelial channels, and transcellular vesicular cles involved in transcytosis, which appear to transport. The cells are joined by continuous be neutral. Thus, the endothelial surface pres¬ tight junctions that prevent passage of mole¬ ents to the blood a mosaic of microdomains cules through the intercellular clefts. In this of varying charge. It is speculated that these and other respects, the endothelium of brain may be able to sort macromolecules according capillaries is similar to epithelia. It has a low to their differing charge. Cationic tracers are permeability to many polar solutes and a high 388 BLOOD AND LYMPH VASCULAR SYSTEMS Figure 12-19. Electron micrograph of a typical capillary from guinea pig pancreas. The entire circumference is made up of a single endothelial cell. There is a thin basal lamina and a few associated collagen fibers. No pericyte is present in this plane of section. (Micrograph from Bolender, R.J. 1974. J. Cell Biol. 61:269.) transcellular gradient for proteins, ions, and cells. Capillaries invading transplants of other amino acids. cell types do not. The barrier obviously cannot be absolute A blood-ocular barrier and a blood-thymus because the brain, like other tissues, is depen¬ barrier have been shown to depend on prop¬ dent on the blood to supply its metabolic sub¬ erties similar to those of the brain. In the thy¬ strates and to remove its wastes. The transen- mus, segments of the microvasculature only dothelial movement of glucose, amino acids, a few millimeters apart have very different nucleosides, and purines have been exten¬ permeability properties. The endothelium sively studied and appears to depend on spe- prevents access of circulating macromolecules cibc carrier-mediated transport. The cells ex¬ to the lymphocytes in the cortex, whereas the hibit a polarity with different transport endothelium of capillaries in.the medulla are systems in the lumenal and basal membranes. freely permeable to the same electron-opaque For example, Na+, K+ —ATPase is found in probes that are excluded from the cortex. the basal and not in the apical plasma mem¬ brane of endothelial cells in brain capillaries. There is now evidence that the barrier SECRETORY FUNCTIONS OF properties of brain capillaries are not intrinsi¬ THE ENDOTHELIUM cally determined but are induced by a product of astrocytes, a type of glial cell that is closely The endothelium of blood vessels was long associated with the capillaries of the brain. believed to have a rather passive role, simply If clumps of astrocytes are implanted in the providing a smooth nonthrombogenic lining anterior chamber of the eye, the capillaries to facilitate the flow of blood. It is now known growing from the iris into the transplant de¬ to secrete several components of the underly¬ velop tight junctions between the endothelial ing extracellular matrix, including fibronec-  BLOOD AND LYMPH VASCULAR SYSTEMS 389 Figure 12 20. Electron micrograph of capillary endothelium, illustrating the small vesicular invaginations of the luminal and basal membranes that are characteristic of capillaries in muscle. (From Fawcett, D.W. 1965. J. Histochem. Cytochem. 13:75.). The inset shows two such vesicles on opposite surfaces of the endothelium at high magnification (From Bruns R. and G.E. Palade. 1968. J. Cell Biol. 37:244.) ' tin, laminin, collagens, II, IV, and V. Other of injury to blood vessels. The von Willebrand products of the endothelium are involved in factor facilitates the binding of platelets to the blood clotting, emigration of neutrophils, re¬ endothelium to form a hemostatic plug and, circulation of lymphocytes, and maintenance thus, plays an important role in limiting blood of vascular tone. loss from damaged vessels. The functional versatility of the endothe¬ Small arteries respond to the shear stress lium long went unsuspected because the cells associated with an increased rate of blood flow lack the degree of development of the endo¬ by vasodilatation. This response was formerly plasmic reticulum and Golgi complex that is attributed to local release of a diffusable sub¬ expected of secretory cells, and they usually stance acting on the smooth muscle of the have no secretory granules in their cytoplasm. vessel wall to decrease vascular tone. Pending The majority of their products are secreted its isolation and characterization, this hypo¬ constitutively. An exception is the von Wille- thetical mediator was called the endothelium- brand factor, already referred to in describing derived relaxing factor (EDRF). It has now been the ultrastructure of arteries. Small amounts discovered that endothelial cells synthesize ni¬ of this large glycoprotein may be secreted con¬ tric oxide (NO) from L-arginine and this acti¬ stitutively, but it also follows the regulated se¬ vates an enzyme that causes relaxation of cretory pathway, being stored in atypical se¬ smooth muscle. The postulated endothelium- cretory granules, called Weibel—Palade derived relaxing factor is now considered to bodies. These are believed to discharge their be nitric oxide. contents into the blood by exocytosis in re¬ Endothelium responds to anoxia by release sponse to cytokines such as interleukin-1 and of vasoconstrictor substances. The most po¬ tumor necrosis factor that are liberated at sites tent of these is endothelin-I, a peptide that binds  Capillary lumen Marginal fold Basal lamina Endothelial junction pMSi BHliiR Figure 12-21. Electron micrograph of a capillary from cardiac muscle, illustrating the interdigitating cell junction and a marginal fold. Figure 12-22. Micrograph of the junction between two endothelial cells in a muscle capillary. At the arrows, the opposing membranes are joined to form an occluding junction. (Micrograph courtesy of E. Weihe.) 390  ,Pericyte Figure 12 23. Schematic representation of the two most common types of capillaries. (A) The continuous or muscle ype with an uninterrupted endothelium. (B) The fenestrated type in which the endothelium varies in thickness and the thinnest areas have multiple small pores closed by an exceeding thin diaphragm. (After Fawcett D W 1962 In J L Orbison and D. Smith, eds. Peripheral Blood Vessels. Baltimore, Williams and Wilkins) Figure 12-24. Micrographs of segments of the endothelium from the two types of capillaries. (A) Endothelium of the muscle- type capillary has vesicular invaginations of both adluminal and abluminal plasma membranes (arrows). (B) Endothelium of a fenestrated capillary from the lamina propria of the colon is very thin and has pores closed by a thin diaphragm (Micrographs courtesy of E. Weihe.) 391 392 BLOOD AND LYMPH VASCULAR SYSTEMS Figure 12-25. Replica of a freeze-fracture preparation of a fenestrated capillary. The extensive surface view of the cleaved membrane of an endothelial cell shows fenestrated areas separated by nonfenestrated areas. Note the uniform size and spacing of the pores. (Micrograph courtesy of S. McNutt.) to smooth muscle of arteries and is several (TNF, II-1) activate endothelial cells to synthe¬ times as effective in the elevation of blood size and incorporate in their membrane, inter¬ pressure as angiotensin-II, the systemic regu¬ cellular-adhesion molecules (ICAM-1, ICAM-2), lator of vascular tone. Endothelin-I has a hy¬ and platelet-activating factor (PAF). Concur¬ pertensive action of relatively long duration. rently with the synthesis of PAF, P-selectin is It is not yet clear whether it is involved in released from granules in the endothelial cy¬ regulation of the cardiovascular system as a toplasm and inserted in the membrane. The whole or is produced locally in defensive initial arrest of circulating leukocytes at sites events such as haemostasis after injury. of inflammation is mediated by their binding The leukocytes are transported in the blood to P-selectin on the endothelium and binding but carry out their functions in the tissues. To of F-selectin on their surface to endothelial reach their ultimate destinations, they must receptors, causing the leukocytes to roll slowly first adhere to the endothelium and then mi¬ over the surface. PAF on the endothelial cells grate between its cells. The interactions of leu¬ also serves as a signal inducing a structural kocytes with the endothelium of postcapillary change in the integrins on the leukocytes that venules are early and essential events in in¬ increases their binding affinity for the ICAMs flammation. Circulating polymorphonuclear on the endothelium, resulting in tighter bind¬ leukocytes normally express on their plasma ing and cessation of their rolling. PAF also membrane-adhesion molecules called L-selec- enhances the responsiveness of leukocytes to tin and B2-integrins (CHI la—CH18 and chemotactic factors emanating from the site CHI lb—CHI8). These lectins are capable of of bacterial invasion. After adhering to the binding to receptors on the surface of endo¬ endothelium, they become polarized and mi¬ thelial cells at sites of inflammation. Bacterial grate through the endothelium to ingest and lipopolysaccharide, histamine, and cytokines destroy the bacteria.  BLOOD AND LYMPH VASCULAR SYSTEMS 393 VESICULATION OF THE PLASMALEMMA FORMATION OF CHANNELS AND FENESTRAE Figure 12-26. Alternate models for transport of water-soluble molecules across the endothelium. (A) Continuous formation of plasmalemmal vesicles followed by detachment, transit, and fusion with the membrane on the other side of the endothelium. (B) Transport mediated by a separate cytoplasmic population of vesicles, possibly of Golgi origin, which undergo transient fusion and fission first at one surface and then at the other, without mixing their membrane with the plasmalemma. This would not require massive movement of membrane from one surface to the other. (C) Transcellular passage involving fusion of vesicles to form channels or formation of fenestrate in thin areas of the endothelium. Current opinion favors (A) and/or (C). (Redrawn after Simionescu, N. and M. Simionescu. 1981. In H.H. Ussing, N.B. Bindslev, and O. Sten-Knudsen, eds. Water Transport Across Epithelia. Copenhagen, Munksgaard.) lium into preexisting large, thin-walled em¬ SINUSOIDS bryonic vessels. The walls of the resulting vas¬ cular channels, therefore, conform to the The vascular channels in the liver, bone irregular spaces between the epithelial com¬ marrow, certain endocrine glands, and ponents of the organ. Macrophages may be lymphoid organs are sinusoids of relatively incorporated in the sinusoidal endothelium. large caliber and irregular cross-sectional out¬ Because of their active endocytosis and phago¬ line. Unlike capillaries that are cylindrical in cytosis, sinusoids have traditionally been form, sinusoids vary in shape and usually con¬ grouped together with the monocyte-derived form to the spaces between the epithelial macrophages of the body as components of sheets and cords of the organ that they supply. the so-called reticulo-endothelial system. Their form is a consequence of their mode of In some lymphoid organs, the sinusoidal development. Capillaries develop as branch¬ endothelium is extremely thin but continuous. ing cellular cords that secondarily acquire a In endocrine glands, its cells present a mosaic lumen and then grow by addition of vasofor¬ of fenestrated and unfenestrated areas. The mative cells at their ends. In liver and other hepatic sinuoids are unique in having larger epithelial organs, sinusoids develop during fenestrations of varying size and shape organogenesis by ingrowth of cords of epithe¬ through which the blood plasma has direct 394 BLOOD AND LYMPH VASCULAR SYSTEMS access to the liver cells with no interposed per¬ are not nearly as well developed in veins as meability barrier. they are in arteries, and connective tissue com¬ ponents are more prominent. In certain veins, a tunica media cannot be identified. VEINS From the capillaries, blood is carried back VENULES AND SMALL VEINS to the heart in the veins. These normally ac¬ company the corresponding arteries (Fig. 12— Capillaries converge to form postcapillary 27, and as they progress toward the heart they venules of slightly larger size (15—20 /am) (Fig. increase in diameter and their walls become 12—28). The ultrastructure of the wall of these thicker. Because veins are more numerous vessels is not significantly different from that than arteries and have a larger lumen, the of capillaries (Fig. 12-29). It consists of very venous system has a much greater capacity thin endothelium surrounded by reticular fi¬ than the arterial system. The walls of veins bers and pericytes. Although it is not evident are thinner, more supple, and less elastic than in histological sections, the pericytes differs those of arteries. Thus, in histological sections, somewhat from those of capillaries in their veins are usually collapsed and have a slit-like shape and interrelationships. In scanning lumen, unless a special effort has been made electron micrographs, their multiple to fix them in distension. branching processes form a rather elaborate For descriptive purposes, it is customary to loose network around the vessel (Fig. 12—30). distinguish three categories: small, medium, In larger venules, these give way to smooth and large veins. However, this subdivision is muscle cells. In venules about 50 fxm in diame¬ not entirely satisfactory because the structure ter, circumferentially oriented smooth muscle of the wall is not always closely correlated with cells are spaced some distance apart, but they the diameter of the vessel. Veins in the same become more closely spaced in vessels of category show greater variation in their struc¬ larger size. In larger venules and small veins, ture than do arteries, and the same vein may smooth muscle forms a more-or-less continu¬ vary in the structure of its wall in different ous layer, but the cells are more irregular in segments along its length. shape and are spaced farther apart than those Most authors distinguish three layers in the of arterioles (Fig. 12—31). wall of veins: tunica intima, tunica media, and Not all of the exchange between the blood tunica adventitia, as in arteries. However, the and the tissues takes place in the capillaries. boundaries of the layers are often quite indis¬ The postcapillary venules also participate in tinct. The muscular and elastic components this function. Indeed, their wall seems to be Endothelium Small artery Vein Elastica interna Smooth muscle Muscle of tunica media at cell Fat cell Adventitia Figure 12-27. Cross section through a small artery and its accompanying vein from the submucosa of the human intestine.  BLOOD AND LYMPH VASCULAR SYSTEMS 395 Figure 12-28. Photomicrograph of a thin-spread intact mesentery showing a nerve, venule, and capillaries. even more permeable. When particulate trac¬ lial venules. This local specialization of the ves¬ ers are injected intravascularly, the first parti¬ sels is an important component of the mecha¬ cles found outside of the vessels are not at the nisms that ensure localization of specific capillaries, but are along slightly larger vessels categories of lymphocytes in the lymphoid tis¬ interpreted as venules. This segment of the sues. For example, T-lymphocytes predomi¬ vascular system is also the preferential site for nate in lymph nodes, whereas B-lymphocytes emigration of leukocytes from the blood into are most abundant in Peyer’s patches. This the tissues. These vessels are also especially selective distribution depends on the fact that susceptible to the effects of histamine, seroto¬ lymphocytes possess type-specific molecules nin, and other substances known to increase (homing receptors) on their surface. As blood vascular permeability. If one of these sub¬ circulates, lymphocytes destined to home into stances is injected locally into an animal that the submucosal lymphoid tissue bind to type- has previously received an intravascular injec¬ specific molecules on the luminal surface of tion of an electron-opaque particulate tracer, the high-endothelial cells that recognize the the particles accumulate in small gaps formed ligand on the surface of the lymphocytes. by retraction of endothial cells of the venules, Having adhered to the high-endothelial cells, thus marking the sites of increased permeabil¬ the lymphocytes then migrate through the ity (Fig. 12—32). Such leaks can occasionally wall of the vessels into the surrounding be found in typical capillaries but much less lymphoid tissue. A protein molecule of 58- often than in venules. There is some evidence 60 kD that is responsible for lymphocyte of a gradient in permeability from the arterial homing to mucosal lymphoid tissue has been to the venous side of the capillary bed which isolated and partially characterized. Recogni¬ extends into the postcapillary venules. tion molecules which are specific for lympho¬ In lymph nodes and submucosal lymphoid cytes bearing “addresses” to other tissues accumulations called Peyer’s patches, the post¬ having high-endothelial cells, such as periph¬ capillary venules have a unique structure. eral lymph nodes, and the synovium of in¬ Their endothelial cells are not squamous but flamed joints, will no doubt be identified in cuboidal. Such vessels are called high-endothe¬ the future. 396 BLOOD AND LYMPH VASCULAR SYSTEMS Figure 12-29. Electron micrograph of a portion of the wall of a small venule from the myocardium. The appearance of the thin continuous endothelium is essentially the same as that of a capillary. The nuclear region of the endothelial cell bulges into the lumen. VEINS OF MEDIUM SIZE LARGE VEINS Veins in the size range 2—9 mm include the The large veins include the inferior vena cutaneous and deeper veins of the extremities cava, the portal, splenic, superior mesenteric, distal to the brachial and popliteal, the veins external iliac, renal, and azygos veins. Their of the head, and many of those of the viscera. tunica intima has much the same structure Their tunica intima consists of endothelium, as in medium-sized veins, but in these larger its basal lamina, and associated reticular fibers. trunks, the subendothelial connective tissue It is sometimes bounded externally by a mod¬ may be considerably thicker. It contains scat¬ erately dense network of elastic fibers, but tered fibroblasts and is bounded externally by there is no true elastica interna. In surface a network of elastic fibers. The amount of view, the endothelial cells tend to have elabo¬ smooth muscle in the wall of veins is highly rate interdigitating outlines. The media con¬ variable. Smooth muscle is a prominent com¬ sists of a layer of circular smooth muscle but ponent of the veins in the gravid uterus, and this is thinner and more loosely organized the pulmonary veins have a well-developed than in arteries. Numerous longitudinal colla¬ media containing circular smooth muscle, but gen fibers and a few fibroblasts intermingle in the great majority of large veins, a media with, and tend to separate, the smooth muscle is lacking and a thick adventitia makes up the cells. The tunica adventitia of medium-sized greater part of the thickness of the wall. veins is usually their thickest layer and consists Smooth muscle is entirely absent in veins of of bundles of collagen and networks of elastic the meninges, retina, placenta, corpora cav¬ fibers. A few longitudinally oriented smooth ernosa, and spongiosa of the penis. Where muscle cells may found between the adventitia vessels are shielded from pressure of sur¬ and the media. rounding structures, there is very little smooth  BLOOD AND LYMPH VASCULAR SYSTEMS 397 Figure 12-30. The pericytes differ in their form along the length of the microvasculature, from the arterial to the venous end. Here in a postcapillary venule of a cat mammary gland, the highly branched pericyte processes form a lace-like network over the surface of the vessel. (Micrograph from Fujiwara, T. and Y. Uehara. 1984. Am. J. Anat. 170:39.) muscle in their wall. On the other hand, the to supply oxygen to their tissues. These are superficial veins of the legs have a rather well- more numerous and extend more deeply into developed media. This may possibly be an ad¬ the wall of veins than they do in arteries. aptation to resist distension due to the resis¬ tance to flow that is attributable to the force of gravity. The great saphenous vein of the VALVES OF VEINS lower extremity has circular smooth muscle in its media and may also have an inner layer Many medium-sized veins have valves that of longitudinal fibers. prevent flow of blood away from the heart. The thick adventitia of larger veins is rich Each of the two opposing semilunar valve in elastic fibers and bundles of collagen that leaflets is a thin fold of the intima, internally are oriented, for the most part, longitudinally. reinforced by a thin layer of collagen and a In the inferior vena cava, the collagen fibers network of elastic fibers that are continuous are reported to have a spiral course that is with those in the intima of the vessel wall (Fig. believed to facilitate the slight lengthening 12-33). On the side toward the vessel wall, the and shortening that the vessel undergoes in endothelial cells are elongated transversely, the ascent and descent of the diaphragm. The whereas on the other side, the long axis of the inferior vena cava is also exceptional in that cells is longitudinal. The space between the its adventitia contains scattered longitudinal valve and the vessel wall is called the sinus of bundles of smooth muscle. Where the pulmo¬ the valve. Just above the arc of attachment of nary veins and the vena cava enter the heart, each valve cusp, the wall of the vein is thinner cardiac muscle extends a short distance into and slightly expanded. In distended veins, this their adventitia. thin region of the wall bulges slightly, making Minute vessels, called vasa vasorum, pene¬ it possible to detect the location of valves in trate the wall of both large arteries and veins intact vessels with the naked eye. Figure 12-31. Scanning micrograph of a large venule joi