Blood Vessels Part I - General Pathology Prefinals PDF

FIRST SEMESTER: GENERAL PATHOLOGY PREFINALS BLOOD VESSELS PART I #02 Floranne Margaret L. Vergara, MD, FPSP...

FIRST SEMESTER: GENERAL PATHOLOGY PREFINALS BLOOD VESSELS PART I #02 Floranne Margaret L. Vergara, MD, FPSP OCT - 19 - 2023 OUTLINE I Vascular Structure and Function II Vascular Wall Response III Hypertensive Vascular disease IV Arteriosclerosis V Atherosclerosis VI APA References I. RECAP: VASCULAR STRUCTURE AND FUNCTION Two principal mechanisms that underlie vascular disease: 1. Narrowing (stenosis) or complete obstruction of vessel lumens (eg. atherosclerosis, thrombosis, embolism) 2. Weakening of vessel walls, leading to dilation or rupture Atherosclerosis → affects mainly elastic and muscular arteries Hypertension → affects small muscular arteries and arterioles Figure 1. The vasculature A. LAYERS OF VESSELS Source: Robbins; see appendix Basic constituents of the walls of blood vessels are: Arteries → Endothelial cells, smooth muscle cells, extracellular Divided into three types based on their size and structural matrix including elastin, collagen, and features glycosaminoglycans 1. Large or elastic arteries Three concentric layers of blood vessels: ▪ Aorta, major branches of aorta, innominate, → Intima, media, adventitia subclavian, common carotid, iliac, and pulmonary 1. Intima. Normally consists of a single layer of endothelial arteries cells attached to a basement membrane with a thin 2. Medium-sized or muscular arteries underlying ECM; ▪ Small branches of the aorta → Demarcated from the media by internal elastic lamina 3. Small arteries 2. Media of elastic arteries. Arranged in layers of lamellar ▪ < 2 mm in diameter units of elastin fibers and SMCs akin to tree rings. 4. Arterioles → The high elastin content allows the vessel to expand ▪ 20 to 100 um in diameter during systole and recoil diastole. ▪ Within tissues and organs → There is loss of elasticity with aging, therefore the aorta and larger arteries become less compliant. Capillaries → Arteries of older individuals also often become tortuous Slightly smaller (5um) than the diameter of a red blood cell and dilated (ectatic) (7 to 8um) → Media of Muscular arteries. composed predominantly Composition of circumferentially oriented SMCs. Vasoconstriction or → Endothelial cell lining but no media vasodilation of these vessels is regulated by inputs → Variable number of pericytes (cells that resemble SMC) from the autonomic nervous system and local → Large cross-sectional area and a relatively low flow metabolic factors. rate. → Arterioles are the principal points of physiologic The combination of thin walls and slow flow makes resistance to blood flow. The resistance to fluid flow capillaries suitable for exchange of diffusible substances is inversely proportional to the fourth power of the between blood and tissues diameter (halving diameter increases resistance 16x) Functionally useful oxygen diffusion is limited to a distance ▪ Small decrease in the lumen size of arterioles of only approximately 100 um caused by structural changes or vasoconstriction Tissues with high metabolic rates such as myocardium can have profound effects on blood pressure. have the highest density of capillaries Adventitia. This layer lies external to the media. duh → Separated from the media by a well-defined external Postcapillary venules elastic lamina. Capillary beds → postcapillary venules → collecting → Consists of loose connective tissue and nerve fibers venules → small → medium → large veins → Diffusion of oxygen and nutrients from the lumen is Where vascular leakage and leukocyte exudation occur adequate to sustain thin-walled vessels and the during inflammation innermost SMCs of all vessels → In large- and medium-sized vessels, however, small Veins arterioles within the adventitia (called vasa Have larger diameter, larger lumens, and thinner and less vasorum—literally, “vessels of the vessels”) perfuse well-organized walls the outer half to two-thirds of the media. → Augment the capacitance of the venous side of the circulation, which on average contains about two-thirds of total blood volume Reverse flow is prevented by venous valves (TWG) JAO, DATUKALI, GUADALUPE, FAJARDO, CORTEZ | (TEG) | (TC) TAGANAS NMD2026  Lesson 2: Blood Vessels Part I NMD2026 Lymphatics II. VASCULAR WALL RESPONSE TO INJURY Thin-walled, endothelium-lined channels that drain lymph → Lymph: water, electrolytes, glucose, fat, proteins, and inflammatory cells Interstitium of tissues → bloodstream via thoracic duct Function → Transport interstitial fluid and inflammatory cells from the periphery to lymph nodes, thereby facilitating antigen presentation and cell activation in the nodal tissues—and enabling continuous monitoring of peripheral tissues for infection → Can also disseminate disease by transporting microbes or tumor cells to distant sites Figure 3. Response to vascular injury Source: Robbins; see appendix Endothelial cells Form a specialized simple squamous epithelium lining for blood vessels Morphologic appearances: → Liver sinusoids and renal glomeruli: fenestrated ▪ Facilitate filtration → CNS: tight junction ▪ Creates an impermeable blood-brain barrier Figure 2. Key concepts: vascular structure and function Source: Robbins EC functions: → Maintains blood in a fluid state due to nonthrombogenic B. CONGENITAL VASCULAR ANOMALIES surface that → Modulate medial SMC tone (influence vascular 1. Developmental or berry aneurysms resistance) → These anomalies occur in cerebral vessels → Metabolize hormones such as angiotensin → Can cause fatal intracerebral hemorrhage when → Regulate inflammation ruptured → Affect the growth of other cell types, particularly SMCs 2. Arteriovenous fistulas → Rapid egress of fluids, electrolytes, and protein → Direct connections (usually small) between arteries and ▪ Due to contraction of ECs by vasoactive agents veins that bypass capillaries (e.g., histamine) → Causes of AV fistula ▪ Leukocytes can slip between ECs in inflammation ▪ Developmental defects (most common) ▪ Rupture of arterial aneurysm into the adjacent vein Endothelial activation ▪ Penetrating injuries that pierce arteries and veins → Occurs when ECs respond to various stimuli by ▪ Inflammatory necrosis of adjacent vessels adjusting their steady-state (constitutive) functions and → Surgically generated arteriovenous fistulas provide by expressing newly acquired (inducible) properties. vascular access for chronic hemodialysis → Inducers of endothelial activation: ★ Arteriovenous fistulas can rupture, like berry aneurysm ▪ Cytokine, bacterial products, hemodynamic stress, → Large or multiple arteriovenous fistulas become lipid products viruses, hypoxia and complement clinically significant by shunting blood from the arterial components to the venous circulations, forcing the heart to pump ▪ May lead to septic shock in severe cases additional volume and leading to high-output cardiac → Activated ECs express adhesion molecules, produce failure. cytokines, chemokines, growth factors, vasoactive 3. Fibromuscular dysplasia molecules → A focal irregular thickening in medium and large ECs influence the vasoreactivity of the underlying SMCs muscular arteries including renal, carotid, splanchnic, through the production of both vasodilating (relaxing) and vertebral vessels factors (e.g., nitric oxide [NO]) and vasoconstrictive factors → Cause: unknown (e.g., endothelin) → Segments of the vessels are focally thickened by a combination of medial and intimal hyperplasia and Endothelial dysfunction fibrosis, resulting in luminal stenosis → Refers to an alteration in endothelial → Renovascular hypertension → in renal arteries phenotype—seen in many different → “String of beads” appearance on angiography conditions—that is often both proinflammatory and ▪ Lead to vascular outpouching (aneurysms) that can prothrombogenic rupture → Certain forms of endothelial dysfunction are rapid in 4. Anomalous coronary artery origin onset (within minutes), reversible, and independent of → Occurs from a developmental anomaly in which both new protein synthesis (e.g., EC contraction induced by coronary arteries arise over the same coronary cusp of histamine and other vasoactive mediators that cause the aortic valve gaps in venular endothelium → Usually benign → Upregulation of adhesion molecules involve alterations → Coronary vessel passes between the aorta and in gene expression and protein synthesis and may pulmonary artery which can be squeezed during require hours or even days to develop exercise, limiting blood flow → death 2 of 12  Lesson 2: Blood Vessels Part I NMD2026 Vascular smooth muscle cells (SMC) The predominant cellular element of the vascular media Functions: → Have the capacity to proliferate when appropriately stimulated → Synthesize collagen, elastin, and proteoglycans and elaborate growth factors and cytokines → Responsible for the vasoconstriction or dilation that occurs in response to physiologic or pharmacologic stimuli Figure 6. Key concepts: vascular wall cells to injury Source: Robbins III. HYPERTENSIVE VASCULAR DISEASE Systemic and local tissue blood pressures must be maintained within a narrow range Low pressure → inadequate organ perfusion → tissue death High pressure (hypertension) → end-organ damage → One of the major risk factors for atherosclerosis Both systolic and diastolic bp are important in determining Figure 4. Endothelial cell properties and functions risk Source: Robbins New Guidelines/criteria in measuring Blood pressure A. INTIMAL THICKENING No rigidly defined threshold level of blood pressure Vascular injury associated with EC dysfunction stimulates identifies those who have an increased risk for SMC recruitment and proliferation and associated ECM cardiovascular disease synthesis—results in intimal thickening that can Clinically significant hypertension: individuals with compromise vascular flow. → Diastolic pressure: >80 mmHg, or Endothelial cells involved in repair can migrate from → Systolic pressures: >120 mmHg adjacent uninjured areas into denuded areas. Approximately 46% of individuals in the general population Medial SMCs or circulating smooth muscle precursor cells are therefore hypertensive also migrate into the intima, proliferate, and synthesize However, such cutoffs do not reliably assess risk in all ECM the same way that fibroblasts fill in a wound—results patients in neointima Neointima → typically covered by ECs; occurs with any Causes of hypertension form of vascular damage or dysfunction ~10% of the patients have secondary hypertension → Intimal thickening is a response to any insult resulting from underlying renal or adrenal disease, renal artery stenosis, etc. → E.g., primary aldosteronism, Cushing syndrome, pheochromocytoma ~90% is idiopathic—so-called essential hypertension → Multifactorial disorder resulting from the cumulative effects of multiple genetic polymorphisms and interacting environmental factors Hypertension can cause: → Atherosclerosis → Hypertensive heart disease: cardiac hypertrophy & heart failure → Multi-infarct dementia → Aortic dissection → Renal failure Figure 5. Basal and activated endothelial cell states Source: Robbins Neointimal SMCs in contrast to medial SMCs Neointimal SMCs are more proliferative, with increased biosynthetic capabilities and reduced contractile function. Neointimal SMC behavior is regulated by cytokines and growth factors derived from platelets, ECs, and macrophages, as well as thrombin and activated factors. Neointimal SMCs can return to a nonproliferative state. Figure 7. Causes of hypertension Source: Robbins 3 of 12  Lesson 2: Blood Vessels Part I NMD2026 Hypertension is asymptomatic until late in its course, and even severely elevated pressures can be clinically silent RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM for years. Malignant Hypertension a Renin is a proteolytic enzyme produced by renal → Occur in a small percentage of hypertensive persons juxtaglomerular cells; renin is released in response to: (5%) showing a rapidly rising BP that leads to death Low blood pressure in afferent arteriole Elevated levels of catecholamines within 1-2 years if left untreated Low sodium levels in DCT (due to low GFR when cardiac → Characterized by severe pressure elevations (i.e., output is low) systolic pressure more than 200 mm Hg, diastolic pressure more than 120 mm Hg), renal failure, and b Renin cleaves plasma angiotensinogen to angiotensin I, which retinal hemorrhages and exudates, with or without in turn is converted to angiotensin II by angiotensin-converting papilledema (swelling of the optic nerve that reflects enzyme (ACE) increased intracranial pressures) Angiotensin II raises blood pressure: 1. Inducing vascular contraction A. BLOOD PRESSURE REGULATION 2. Stimulating aldosterone secretion by the adrenal Blood pressure is a function of cardiac output and gland peripheral vascular resistance, both of which are 3. Increasing tubular sodium resorption. influenced by multiple genetic and environmental factors Aldosterone increases sodium resorption (and thus water) in the distal convoluted tubules, which increases blood volume. c The kidney also produces a variety of vascular relaxing sub- stances (including prostaglandins and NO) that can counterbalance the vasopressor effects of angiotensin. d Myocardial natriuretic peptides are released from atrial (dominant contributor) and ventricular (minor contributor) myocardium in response to volume expansion; these inhibit sodium reabsorption in the distal renal tubules, thus leading to sodium excretion and diuresis. They also induce systemic Figure 8. Blood pressure regulation vasodilation. Source: Robbins Table 1. Blood pressure inputs Cardiac output Peripheral resistance Function of stroke volume Regulated predominantly at and heart rate the level of the arterioles by Filling pressure—the most neural and hormonal inputs important determinant of Vascular tone reflects a stroke volume balance between Heart rate and myocardial → Vasoconstrictors contractility (a 2nd factor (endothelin, angiotensin affecting stroke volume) are II, catecholamines), and both regulated by the alpha → Vasodilators (kinins, and beta adrenergic systems prostaglandins, NO). Resistance vessels exhibit autoregulation Bp is fine-tuned by tissue pH and hypoxia to accommodate local Figure 9. Interplay of renin-angiotensin-aldosterone and ANP metabolic demands Source: Robbins; see appendix Source: Robbin’s and Cotran pg. 490; refer to Figure 8 Blood pressure regulation in kidneys Factors released from the kidneys, adrenals, and myocardium interact to influence vascular tone and to regulate blood volume by adjusting sodium balance Kidneys → Filter 170 liters of plasma containing 23 moles of salt daily → 99.5% of the filtered salt must be reabsorbed to maintain total body sodium levels → About 98% of the filtered sodium is reabsorbed by several constitutively active transporters. → Small amount of remaining sodium is subject to Figure 10. Key concepts: blood pressure regulation resorption by the epithelial sodium channel (EnaC), Source: Robbins which is tightly regulated by the RAAS → Kidneys and heart → contain cells that sense changes B. PATHOGENESIS OF HYPERTENSION in blood pressure or volume; release effectors that act Vast majority (90-95%) of hypertension is idiopathic, the to maintain normal BP result of interacting genetic and environmental factors. RAAS pathway Small changes in renal sodium homeostasis, and/or → Pathway that determines net sodium balance vessel wall tone or structure act in combination to cause essential hypertension. Hypertension infrequently has an underlying endocrine basis 4 of 12  Lesson 2: Blood Vessels Part I NMD2026 Mechanism of Secondary Hypertension MORPHOLOGY: 1. Renovascular Hypertension 1. Hyaline arteriosclerosis → Usually caused by renal artery stenosis → Arterioles - homogenous pink hyaline thickening with ▪ Causes decreased glomerular flow and pressure in luminal narrowing → reflect both plasma protein leakage and afferent arteriole increased SMC matrix synthesis in response to chronic → Leads to renin secretion leading to increased blood hemodynamic pressures of hypertension volume and vascular tone via angiotensin and → Vessels of older patients - frequently exhibit hyaline aldosterone pathways arteriosclerosis 2. Primary Hyperaldosteronism → Vessels of patients with hypertension and diabetes - → One of the most common causes of secondary more severe and generalized hyaline arteriosclerosis hypertension → Nephrosclerosis – arteriolar narrowing causes diffuse → Can be idiopathic impairment of renal blood supply and glomerular scarring → Less commonly caused by aldosterone-secreting adrenal adenomas 3. Single Gene Disorders → Can cause severe but rare forms of hypertension → Gene defects affecting enzymes involved in aldosterone metabolism (eg. aldosterone synthase, 11B-hydroxylase, 17a-hydroxylase) ▪ Can lead to increased aldosterone secretion → increase in salt and water resorption, plasma volume expansion → hypertension → Mutations affecting proteins that influence sodium reabsorption ▪ E.g., Liddle Syndrome AKA salt sensitive Hyaline arteriosclerosis hypertension (caused by mutations in an epithelial Na channel protein that increases tubular 2. Hyperplastic arteriosclerosis → occur in severe hypertension reabsorption of sodium in response to aldosterone) → Blood vessels - concentric laminated “onion skin” thickening of the walls and luminal narrowing Mechanisms of Essential Hypertension → Laminations - consists of SMCs with thickened, 1. Genetic factors reduplicated basement membrane → Differences in blood pressure between monozygotic ▪ In malignant hypertension, these are accompanied by and dizygotic twins and genetically related vs adopted fibrinoid deposits and vessel wall necrosis (kidney) children → Single gene disorders cause relatively rare forms of hypertension or hypotension by altering the net sodium reabsorption in the kidney 2. Insufficient Renal Sodium Excretion → May be a key initiating event in essential hypertension in the presence of normal arterial pressure ▪ A final common pathway for the pathogenesis of hypertension → Insufficient sodium → increase fluid volume → increased cardiac output → peripheral vasoconstriction → elevated blood pressure Hyperplastic arteriolosclerosis (onion skin) → Resetting of Pressure Natriuresis - At higher blood pressures, enough additional sodium is excreted by the 3. Pulmonary Hypertension - caused by several entities which kidneys to equal intake and prevent further fluid include: left sided heart failure, congenital heart disease, valve retention → new steady state of sodium balanced disorders, obstructive or intestinal lung disease, and recurrent achieved but at the expense of an increase in blood thrombotic emboli pressure → Arterioles - fibrotic intimal thickening and medial hyperplasia 3. Vasoconstrictive Influences → Factors that induce vasoconstriction or stimuli that cause structural changes in the vessel wall → increase in peripheral resistance → may cause essential hypertension 4. Environmental Factors → Stress, obesity, smoking, physical inactivity, heavy salt consumption are implicated in hypertension C. VASCULAR PATHOLOGY IN HYPERTENSION Hypertension accelerates atherogenesis and causes degenerative changes in the walls of large and medium arteries that can lead to aortic dissection and cerebrovascular hemorrhage Three forms of small vessel disease are hypertension related Figure 11. Key concepts: hypertension Source: Robbins 5 of 12  Lesson 2: Blood Vessels Part I NMD2026 → Estrogen replacement: no benefit; may increase IV. ARTERIOSCLEROSIS cardiovascular risk in some older women Hardening of the arteries; generic term for arterial wall postmenopause thickening and loss of elasticity Modifiable Major Risk Factors Four general patterns 1. Hyperlipidemia 1. Arteriolosclerosis – small arteries and arterioles → Specifically hypercholesterolemia ▪ May cause downstream ischemic injury → Sufficient to initiate lesion development even in the ▪ Hyaline and hyperplastic absence of other risk factors 2. Mönckeberg medial sclerosis → Major component: LDL Cholesterol ▪ Calcification of medial walls of muscular arteries ▪ “bad cholesterol” − Starts at internal elastic membrane ▪ Complex that delivers cholesterol to peripheral ▪ Adults >50 y/o tissues 3. Fibromuscular intimal hyperplasia → HDL ▪ Driven by inflammation or mechanical injury ▪ Complex that mobilize cholesterol from periphery > ▪ Occur in muscular arteries transport to the liver for excretion ▪ May be a healing response ▪ "good cholesterol" > correlate with reduced risk ▪ Major long term limitation of solid-organ transplants Plasma cholesterol levels 4. Atherosclerosis → Raises plasma cholesterol levels ▪ Translates to gruel and hardening ▪ High dietary intake of cholesterol and saturated fats V. ATHEROSCLEROSIS (egg yolks, animal fats, and butter) ▪ Baked goods and margarine Underlies the pathogenesis of coronary, cerebral, and − Trans-unsaturated fats peripheral vascular disease → Lowers plasma cholesterol levels Likelihood is determined by acquired, inherited and ▪ Diet low in cholesterol gender- and age- associated risk factors ▪ Diet high in polyunsaturated fat (omega-3 fatty Atheromas acid/fish-oil) → AKA atheromatous or atherosclerotic plaques ▪ Statins – class of drugs that lower circulating → Are intimal lesions that protrude into vessel lumens cholesterol levels; inhibit HMG-CoA reductase → Consists of a raised lesion with a soft grumous core of HDL Levels lipid covered by a fibrous cap → Increase HDL level ▪ Exercise and moderate consumption of ethanol → Lowers HDL level ▪ Obesity and smoking 2. Hypertension → Both systolic and diastolic levels are important → Increases the risk of IHD by approximately 60% → Most common cause of left ventricular hypertrophy 3. Cigarette smoking Figure 12. Atherosclerotic plaque → One pack of cigarettes or more daily doubles the death Source: Robbins; see appendix rate from IHD → Smoking cessation reduces risk A. RISK FACTORS 4. Diabetes mellitus → Induces hypercholesterolemia > markedly increases Framingham Heart Study → one of the prospective the risk of atherosclerosis analyses that identified risk factors → Incidence of MI is 2x as high vs non-diabetic Risk factors may be constitutional (less controllable), or → Increased risk of stroke acquired → 100x increased risk of atherosclerosis-induced Constitutional Risk Factors gangrene of lower extremities 1. Genetics → Most important risk factor Additional Risk Factors → Certain Mendelian disorders are strongly associated 1. Inflammation with atherosclerosis (eg., familial hypercholesterolemia) → Linked with atherosclerotic plaque formation and 2. Age rupture → Manifest in middle age or later → C-Reactive Protein (CRP) → Myocardial infarction has a fivefold increase of ▪ Marker of inflammation correlate with IHD risk incidence in 40-60 years old ▪ Strong, independent marker of risk for → In aging, there is a tendency for outgrowth of − MI, Stroke hematopoietic clones (clonal hematopoiesis of − Peripheral arterial disease indeterminate potential or CHIP) carrying mutations − Sudden cardiac death ▪ May affect DNA modifications and transcriptional ▪ Acute phase reactant synthesized by the liver regulation → ultimately influence risk of developing ▪ Simplest to measure hematologic malignancies ▪ One of the most sensitive → CHIP mutations affecting cellular proliferation can ▪ Useful marker for gauging effect of risk reduction impact the inflammatory response of mononuclear measures: reduce CRP level cells, influencing atherogenesis 2. Hyperhomocysteinemia 3. Gender → Serum homocysteine level - correlate with → Premenopausal women → protected against ▪ Coronary atherosclerosis atherogenesis compared to age-matched men ▪ Peripheral vascular disease → Uncommon in premenopausal women unless ▪ Stroke predisposed by diabetes, hyperlipidemia, severe ▪ Venous thrombosis hypertension → Homocystinuria → an IEM result to increased → Incidence after menopause increases circulating homocysteine (>100 μmol/L) 6 of 12  Lesson 2: Blood Vessels Part I NMD2026 3. Metabolic syndrome [ROBBINS] Pathogenesis of Atherosclerosis → Central obesity Atherosclerosis progresses in the following sequence: → Characterized by 1. Endothelial injury and dysfunction ▪ Cardiac risk factors 2. Accumulation of lipoproteins − Insulin resistance 3. Monocyte adhesion to the endothelium − Hypertension 4. Platelet adhesion − Dyslipidemia (elevated LDL & depressed HDL) 5. Factor release from activated platelets, macrophages, and ▪ Endothelial dysfunction and/or thrombosis vascular wall cells − Hypercoagulability 6. SMC proliferation, ECM production, and recruitment of T cells − Pro-inflammatory state 7. Lipid accumulation 4. Lipoprotein A [Lp(a)] 8. Calcification of ECM and necrotic debris → Altered form of LDL → Contains apolipoprotein B-100 portion of LDL linked to Table 2. Pathogenesis of Atherosclerosis apolipoprotein A (apo A) Cornerstone of the response-to-injury → Associated with coronary and cerebrovascular disease hypothesis risk Early human lesions begin at sites of → Independent of total cholesterol or LDL level morphologically intact endothelium 5. Factors affecting hemostasis Etiologic culprits include: → Elevated plasminogen activator inhibitor 1 → Toxin from cigarette smoke → Homocysteine → Platelet derived factor & thrombin Endothelial → Inflammatory cytokines 6. Other factors Injury The three most important causes are: → Lack of exercise → Hemodynamic disturbances → Competitive stressful lifestyle ("type A" personality) → Hypercholesterolemia → Obesity → Inflammation ▪ Complicated by HPN, DM and hypertriglyceridemia Increased vascular permeability and decreased HDL Enhanced leukocyte adhesion Altered gene expression B. PATHOGENESIS Plaques tend to occur where there are Response-to-injury hypothesis disturbed flow patterns → Atherosclerosis as a chronic inflammatory and healing → At ostia of existing vessels response of the arterial wall to endothelial injury → Branch points → Along the posterior abdominal aorta → Early human lesions begin at sites of morphologically Hemodynamic where flow patterns are disturbed and intact endothelium disturbances non-laminar; ★ Endothelial loss due to any kind of injury ⇒ Intimal ▪ Laminar non-turbulent flow increases thickening ⇒ high-lipid diets ⇒ typical atheromas the production of transcription factors, like Kruppel-like-factor-2 (KFL2) that Endothelial injury & dysfunction turn on atheroprotective genes and Etiologic culprits include: turn off inflammatory gene transcription → Toxins from cigarette smoke Dyslipoproteinemia (check the previous section) → homocysteine Hypercholesterolemia in atherogenesis: → Inflammatory cytokines Three most important causes of endothelial dysfunction 1. The dominant lipids in atheromatous 1. Hemodynamic disturbances plaques: cholesterol and cholesterol esters 2. Genetic defects in lipoprotein uptake and 2. Hypercholesterolemia metabolism 3. Inflammation (added in the 10th edition of Robbins) → Cause hyperlipoproteinemia ⇒ Endothelial injury leads to increased vascular permeability, associated with accelerated enhanced leukocyte adhesion and altered gene atherosclerosis expression 3. Epidemiologic analyses 1. Hemodynamic disturbances → Significant correlation between severity of → Plaques tend to occur where there are disturbed flow atherosclerosis and LDL, cholesterol patterns and nonlaminar levels ▪ At ostia of exiting vessels 4. Lowering serum cholesterol ▪ Branch points → Slow progression of atherosclerosis and ▪ Along the posterior wall of the abdominal aorta reduce risk of cardiovascular events → Due to disturbed flow patterns, this alters the action of Hypercholes– 5. Lead to premature atherosclerosis transcription factors, promoting atheroma formation terolemia Hyperlipidemia in atherogenesis 2. Dyslipoproteinemia or lipoprotein abnormalities Impaired EC function → Increased LDL cholesterol levels → Due to increased local ROS resulting to: → Decreased HDL cholesterol levels 1) Membrane and mitochondrial damage, → Increased levels of the abnormal lipoprotein (a) 2) acceleration of nitric oxide decay → Dominant lipids in atheromatous plaques Modified LDL ▪ Cholesterol and cholesterol esters → Accumulation of lipoproteins within intima → Hypercholesterolemia → aggregate to be oxidized by free ▪ Lead to premature atherosclerosis radicals produced by inflammatory cells → Foam cells → lipid-filled macrophages ▪ Correlate with severity of atherosclerosis → Binding and uptake of modified LDLs ▪ Lowering serum cholesterol ⇒ slow progression of stimulate the release of growth factors, atherosclerosis and reduce risk of CV events cytokines, chemokines creating an Note: The organization of this section (as well as the Table 2) is derived from inflammatory cycle of monocyte the lecture discussion which is slightly different from the content presented in recruitment and activation the book. Nonetheless, I will incorporate information from the book, despite the → Fatty streaks: lesions containing foam redundancy. Feel free to choose between the two sources for your reading cells preference. 7 of 12  Lesson 2: Blood Vessels Part I NMD2026 Chronic inflammation contributes to the initiation and progression of atherosclerotic lesions Triggered by the accumulation of cholesterol crystals and free fatty acids in the macrophages and other cells → Leads to inflammasome activation resulting in IL1 production (fig 12) Interleukin 1 (IL1) → Proinflammatory cytokine → Recruits and activates mononuclear cells Inflammation including macrophages and T lymphocytes ⇒ leads to local production of cytokines and chemokines that recruit and activate more inflammatory cells Activated macrophages produce reactive oxygen species that enhance LDL oxidation and elaborate growth factors that drive SMC proliferation Activated T lymphocytes in the growing Figure 14. Role of cholesterol crystals in inflammasome activation intimal lesions elaborate inflammatory Source: Robbins; see appendix cytokines which can activate macrophages, ECs and SMCs Evidence linking atherosclerosis with herpesvirus, cytomegalovirus, and Infection Chlamydophila pneumoniae ★ BUT there is no established causal role for infection Intimal SMC proliferation and ECM deposition convert a fatty streak into a mature atheroma and contribute to the progressive growth of atherosclerotic lesions Several growth factors are implicated in SMC proliferation and ECM synthesis, including: Smooth → Platelet-derived growth factor: released by Muscle locally adherent platelets, as well as Proliferation macrophages, ECs and SMCs and Matrix → Fibroblast growth factor Synthesis → Transforming growth factor-α These factors also stimulate SMCs ⇒ synthesize ECM (notably collagen) ⇒ stabilizes atherosclerotic plaques Activated inflammatory cells in atheromas - increase the breakdown of ECM components ⇒ unstable plaques Source: Robbins Pathology Figure 13. Sequence of cellular interactions in atherosclerosis Source: Robbins; see appendix Figure 15. Pathogenesis of atherosclerosis Source: Robbins 8 of 12  Lesson 2: Blood Vessels Part I NMD2026 C. MORPHOLOGY → Deep to fibrous cap ▪ Necrotic core Fatty streaks ▪ Contain lipid (cholesterol), debris from dead cells, foam cells (lipid-laden macrophage and SMCs), Earliest lesion in atherosclerosis fibrin, thrombus, plasma proteins Composed of lipid filled foamy macrophages − Cholesterol content usually present as crystalline Multiple minute flat yellow spots ⇒ coalesce ⇒ elongated aggregates; demonstrated as clefts as a result of streaks being washed away during tissue processing If not sufficiently raised, do not cause any flow disturbance Neovascularization May be exhibited by aortas of infants → Proliferation of small blood vessels Seen in virtually all adolescent even those without known → Located at periphery of lesions risk factor The abdominal aorta is typically involved to a much greater degree than the thoracic aorta In descending order, the most extensively involved vessels are: → Lower abdominal aorta → Coronary arteries → Popliteal arteries → Internal carotid arteries Figure 16. Fatty streak, a collection of foamy macrophages in the intima → Vessels of the circle of Willis Source: Robbins Usually spared: Atherosclerotic plaque → Vessels of the upper extremities Intimal thickening + lipid accumulation = plaque → Mesenteric and renal arteries (except at their ostia) Gross appearance: Clinically important changes → Color Note: thickness and ECM content of fibrous cap will ▪ White-yellow and encroach on the lumen of artery impact the stability or fragility of the plaque and tendency ▪ Red-brown → for superimposed thrombus over to undergo secondary changes ulcerated plaque → Vary in size ⇒ can coalesce to form larger messes 1. Rupture, ulceration, or erosion of the intimal surface ⇒ induce thrombosis → Blood stream is exposed to highly thrombogenic substances → Thrombus may organize and become incorporated into growing plaque 2. Hemorrhage into a plaque → Rupture of the overlying fibrous cap, or of the thin-walled vessels in the areas of neovascularization Figure 17. Atherosclerosis in aorta → Contained hematoma may expand the plaque and Source: Robbins rupture 3. Atheroembolism Lesion → Rupture ⇒ discharge atherosclerotic debris into → Patchy and rarely circumferential bloodstream ⇒ microemboli → Usually involving only a portion of any given arterial 4. Aneurysm formation wall ⇒ appear eccentric → Ischemic atrophy as a result of atherosclerosis-induced pressure → Loss of elastic tissue ⇒ weakness and potential rupture Figure 18. Atheromatous plaque in coronary artery Figure 19. Atherosclerotic plaque rupture Source: Robbins Source: Robbins Four principal components: D. CONSEQUENCES OF 1. Cells - including smooth muscle cells, macrophages, ATHEROSCLEROTIC DISEASE and T cells 2. ECM - including collagen, elastic fibers, and Major consequences of atherosclerosis: proteoglycans → Myocardial infarction (heart attack) 3. Intracellular and extracellular lipids → Cerebral infarction (stroke) 4. Calcifications in later stage plaques (Fig13B,C) → Aortic aneurysms → Peripheral vascular disease (gangrene of the legs) Architecture of the lesion Major targets of atherosclerosis: → Superficial fibrous cap composed of smooth muscle → Large elastic arteries (e.g., aorta, carotid, and iliac cells and relatively dense collagen arteries) → Beneath and side of the cap: or the “shoulder” → Large- and medium-sized muscular arteries (e.g., ▪ More cellular coronary and popliteal arteries) ▪ Contain macrophages, T cells, smooth muscle cells 9 of 12  Lesson 2: Blood Vessels Part I NMD2026 Commonly affected arteries: Susceptibility to rupture → Arteries supplying the heart, brain, kidneys, and lower extremities. Continuous remodeling "Vulnerable plaques" with thin fibrous caps and inflammation are prone to rupture. → Vulnerable plaques are plaques with thin fibrous caps and active inflammatory cells Collagen → Accounts for its mechanical strength and stability → Balance between degradation and synthesis affects integrity of the cap → Turnover and inflammation destabilize plaques Statins may stabilize plaques by reducing inflammation Collagen turnover by metalloproteinases (MMP) → MMP activity is modulated by tissue inhibitors produced by ECs, SMCs, macrophages Adrenergic stimulation → cause increase systemic blood pressure and local vasoconstriction, increasing physical stresses on a given plaque Figure 20. Atherosclerotic plaque formation, activities, outcomes Source: Robbins; see appendix Not all plaque ruptures result in occlusive thrombosis Features of atherosclerotic lesions Atherosclerotic Stenosis Acute Plaque Change Atherosclerotic Stenosis Atherosclerotic plaques in small arteries gradually obstruct vessel lumens, causing compromised blood flow and ischemic injury Early stages involve vessel media remodeling to preserve lumen size. Critical stenosis occurs when occlusion is severe (typically a 70-75% decrease in luminal area) → Consequences include stable angina (chest pain with exertion), diminished arterial perfusion, mesenteric occlusion, bowel ischemia, sudden cardiac death, chronic ischemic heart disease, ischemic Figure 21. Vulnerable plaque Source: Robbins encephalopathy intermittent claudication (diminished perfusion in extremities). Thrombosis ★ Collateral circulation can compensate if stenosis develops Thrombosis, partial or total, associated with disrupted slowly. plaques is central to acute coronary syndromes. Acute Plaque Change → Leads to total occlusion of affected blood vessel in Plaque erosion or rupture results in vascular thrombosis, most serious form leading to acute tissue infarction (e.g., myocardial or → Thrombus can lead to vessel occlusion or partial cerebral infarction) blockage. Plaque changes fall into three general categories: Mural Thrombi and Embolization: 1. Rupture/fissuring, exposing highly thrombogenic plaque → Mural thrombi can embolize, causing small embolic constituents that activate coagulation and induce fragments in the circulation. thrombosis that is often completely occlusive → Thrombin and thrombosis-related factors activate 2. Erosion/ulceration, exposing the thrombogenic smooth muscle cells contributing to the growth of subendothelial basement membrane to blood, atherosclerotic lesions less-frequently inducing fully occlusive thrombosis Vasoconstriction 3. Hemorrhage into the atheroma, expanding its volume Vasoconstriction reduces lumen size and enhances plaque disruption due to increased local mechanical Consequences of Plaque Formation [Unlisted in book] forces Stimulated by: Myocardial infarction and other acute coronary 1. Circulating adrenergic agonists syndromes 2. Locally release platelet contents Susceptibility to rupture 3. EC dysfunction with impaired secretion of Thrombosis endothelial-derived relaxing factors (NO) relative to Myocardial infarction, coronary syndromes contracting factors (endothelin) Asymptomatic plaques can abruptly disrupt, leading to 4. Inflammatory cell mediators acute coronary events. Imaging modalities are being developed to identify these VI. APA REFERENCES lesions early. Vergara (2023). Blood Vessels. College of Medicine, Davao Medical School Healing of subclinical disruptions and thrombi contributes Foundation, Inc. Kumar, V., Abbas, A. K., & Aster, J. C. (2017). Robbins Basic Pathology (10th to atherosclerotic lesion growth. ed.). Elsevier - Health Sciences Division Plaques rupture due to mechanical stresses and complex triggers, involving intrinsic and extrinsic factors → Intrinsic elements: plaque structure and composition → Extrinsic elements: blood pressure, platelet reactivity, and vessel spasm 10 of 12 INDEX: APPENDIX 11 of 12 12 of 12