Lecture 3 Vasculature PDF

Vasculature Physiology 502 Richard M. Mortensen MD PhD Department of Molecular and Integrative Physiology Department of Internal Medicine Metabolism Endocrine and Diabetes Division Nothing to Disclose Objectives 1 ◼ Know the structure of a...

Vasculature Physiology 502 Richard M. Mortensen MD PhD Department of Molecular and Integrative Physiology Department of Internal Medicine Metabolism Endocrine and Diabetes Division Nothing to Disclose Objectives 1 ◼ Know the structure of arteries, veins, capillaries, lymphatic system and overall vascular system. ◼ Know the significance of portal systems ◼ Know the factors in the equation governing blood flow and what can affect these factors. Know the role of arterioles in determining resistance and blood flow distribution. Understand the role of precapillary sphincters ◼ Understand the relationship between cardiac output, pressures changes and resistance. Know the factors that govern cardiac output. ◼ Know the relationship between arterial stiffness and pressure waves and what anatomy correlates with stiffness ◼ Be able to recount the path of blood through the body and the heart ◼ Understand the function of valves in the circulation ◼ Understand the transport of fluid, proteins across capillaries. Understand the formation and role of oncotic pressure ◼ Understand the tissues that have autoregulation of blood flow and the mechanisms responsible ◼ Understand how tissue activity can change blood flow ◼ Understand the factors that change, the direction of change, and mechansims during exercise ◼ Understand the origin of edema and possible treatment ◼ Understand the role of lymph obstruction in formation of edema 2 Objectives 2 ◼ understand the consequences of heart failure and where edema would be present in right or left heart failure ◼ understand the coronary perfusion, what major vessels supply the heart and consequence of their blockage and when in the cycle coronary perfusion occurs ◼ understand leukocyte trafficking, role of venules and lymph. ◼ Understand role of NO and prostaglandins ◼ Understand the mechansims of autoregulatation of blood flow. Know the organs that autoregulate and tissues that do not. Know how tissue activity or neural control can alter tissue perfusion 3 Outline ◼ Vascular System ◼ Coronary Vessels ◼ Vessel Structure ◼ Cerebral Vessels ◼ Arteries ◼ Veins ◼ Capillaries ◼ Lymphatics ◼ Transfer in Capillaries ◼ Cells moving out in post capillary venules ◼ Control of Blood Flow ◼ Local Control of BP ◼ Autoregulation ◼ Tissue demand ◼ Regulation of Blood Flow ◼ Arterioles – vasoconstriction/vasodilation Metabolic activity Neural and endocrine 4  Schematic of Vascular System ◼ All blood goes through heart and lungs ◼ Development of pressure ◼ Excrete CO2 ◼ Oxygenate ◼ Most blood goes through 1 capillary bed ◼ A few have a “Portal” System and 2 capillary beds Hepatic Renal (pituitary – not in diagram) ◼ Missing ◼ Lymph – returns some interstitial fluid to blood Important for lymphocyte circulation 5  Physics of Blood Flow ◼ Bulk flow equation ◼ Law of bulk flow: Q = P/R ◼ Equivalent to CO =  MAP / TPR Q = flow P = pressure drop R = resistance Vasculature supplies resistance ◼ Resistance increases with R = 8L / r4 ◼ Increasing length L L = length of the tube ◼ Increasing viscosity (of blood)   = viscosity of the fluid More leukocytes – leukemia and myeloma r = radius of the tube More rbc – polycythemia vera More platelets – thrombocythemia vasoconstriction / vasodilation to regulate More certain proteins - cryoglobulinemia ◼ Decreasing radius (TO THE 4th POWER) ◼ Poiseuille’s equation: Q = P r4 / 8L Key to control resistance by Vasodilation vasoconstriction Most important factor = RADIUS Arteries 7 ARTERIES ◼ Artery Structure ◼ Tunica Intima Endothelium Basement membrane Elastic tissue/fibers ◼ Tunica Media Smooth muscle cell Elastic tissue ◼ Tunica Externa(or adventitia) Fibroblasts – collagen fibers Adventitia Fat cells, macrophages fibrobasts Vasovasorum (arterioles/capillaries in vessel wall) Vasovasorum Capillaries in vessel wall 8 Surface of Vessel ◼ Coated in Endothelium ◼ Critical to vessel function and regulation 9 Types of Arteries ◼ Large Elastic Arteries ◼ Small wall/diameter ratio ◼ Large amounts of elastin ◼ Aorta, pulmonary, brachiocephalic, and the common carotid artery ◼ Muscular Arteries ◼ Abundant smooth muscle ◼ Femoral, Coronary ◼ Arterioles ◼ Single cell thick squamous epithelium ◼ Media 1 to 6 SMC thick arteriole venule 10 Pulse Pressure – a feature of arterial stiffness ◼ Highest with increased artery stiffness ◼ MAP steadily decreases Elastic A. Muscular A. ◼ Flow aorta to iliac to periphery ◼ Elastic arteries can expand - aorta SBP ◼ Decreases systolic peak MAP ◼ Therefore decreased pulse pressure DBP ◼ When hits less compliant arteries e.g. muscular arteries in iliac branches or brachial artery ◼ Systolic increases ◼ Increased pulse pressure *Complication – there also are reflected waves that can increase systolic Also note – with aging, arteries stiffen and Aorta Iliac pulse pressure increases. Can give rise to 11 isolated systolic hypertension modified https://commons.wikimedia.org/wiki/File:2109_Systemic_Blood_Pressure.jpg Veins 12 Veins Veins have same types of layers as arteries but are much thinner (lower pressure) ◼ Tunica Intima ◼ Endothelium ◼ Basement membrane ◼ Subendothelial layer ◼ Tunica Media ◼ smooth muscle, elastic fibers ◼ Tunica Externa ◼ Collagen ◼ Valves Vena Cava, low power 13 Veinous Valves Determine Blood Flow Direction ◼ Veins have valves ◼ Important for moving blood from lower extremities to heart ◼ Muscles contract ◼ Increasing pressure ◼ Move blood back to heart ◼ Valves determine direction 14 Capillaries 15 Capillary bed between arterioles and venules ◼ Between arterioles and venules is Retinal blood vessel the capillary bed where gas, system nutrients and waste products are Arteriole exchanged Venule Capillary bed Types of Capillaries ◼ Continuous ◼ Most ◼ Fenestrated ◼ Has some holes ◼ RENAL GLOMERULI ◼ Sinusoidal – Large discontinuities ◼ LIVER 17 Continuous and fenestrated capillary walls ◼ Continuous capillary ◼ Transport across Muscle capillary Pinocytotic vesicle (~70 nm) endothelium involves trans-pinocytosis Capillary in the colon ◼ Fenestrated capillary Fenestrations (~80-100 nm) ◼ Renal glomeruli, Diaphragm intestines, pancreas and endocrine glands ◼ Diaphragm is important Limits transport Fenestrated and Discontinuous Endothelium ◼ Fenestrated capillary ◼ Found in Renal glomeruli, intestines, pancreas and endocrine glands Liver sinusoid endothelium Fenestrated capillary Discontinuous capillary ◼ Discontinuous capillary ◼ Sinusoids are specialized large capillaries E30-40 µm), are usually fenestrated or discontinuous, and found in organs like liver, lymph nodes, spleen and bone marrow. Precapillary Sphincters ◼ Precapillary sphincters have a few smooth muscle cells around the vessel that can regulate flow to the capillary ◼ Not in all capillary beds ◼ Metarterioles are small arterioles that connect to capillary bed 20 Abundant capillaries in cardiac muscle ◼ Capillary diameter can be as small as 5 µm, smaller than the diameter of RBCs ◼ RBCs are deformable capillary Summary 22 Anatomy of Cerebral Vessels ◼ Middle cerebral a. come Internal carotid a. fairly straight off internal carotid ◼ Major place emboli will cause blockage ◼ Other arteries get blood flow because of circle of Willis ◼ So you only need one carotid ◼ Vertebral arteries supply some blood flow to circle in human 23 Anatomy of Coronary Arteries ◼ Left main artery supplies left ventricle ◼ Left anterior descending (LAD) supplies anterior majority of LV “widow maker” ◼ Circumflex supplies posterior LV ◼ Right coronary artery supplies right ventricle ◼ Also supplies SA node 24 Lymphatics 25 Lymphatic vessels/capillaries ◼ Low pressure system ◼ Vessel is Thin-walled and usually consist of no more than a thin endothelium. ◼ These endothelial cells are anchored in the surrounding tissues by elastic filaments (not visible by regular light microscopy), that will prevent the collapse of the vessel. Remember that the lymphatic system is a low pressure environment. EM Vascular Bundle Fat cell ◼ Small lymph vessels Lymphatic consisting of no more than a capillary thin endothelium. Arteriole Arteriole ◼ Valves can sometimes be seen. ◼ No rbc Electron micrograph of a lymphatic valve Lymphatic System Summary: ◼ low pressure open system ◼ lined by an endothelium with minimal surrounding connective tissue ◼ Lymph vessels have valves. ◼ normally do not contain erythrocytes, but may contain leukocytes. ◼ channel tissue fluid and leukocytes to lymph nodes and eventually back to the blood circulation. ◼ can provide an avenue for the dispersal of metastatic tumor cells. Transfer in Capillaries, Lymph 29 Overall Circulation ◼ Most pressure drop at arterioles – determine BP ◼ Capillaries have highest surface area, lowest velocity (more time for transfer of materials) ◼ Most blood is in low pressure system ◼ Most blood is in systemic system Velocity of blood within the vascular system 31  Exchange of material across capillary ◼ Diffusion ◼ O2, CO2 ◼ Lipid soluble molecules ◼ Bulk Flow through PORES ◼ Fluid ◼ Ions – Na, K ◼ Glucose, AA ◼ Vesicular Transport ◼ Proteins ◼ Albumin generally doesn’t cross Transfer in the Capillaries ◼ Early part ◼ Fluid moves OUT – higher hydrostatic pressure ◼ Smaller proteins move out ◼ Concentrating non-filtered material Increased albumin Increasing oncotic (colloid) pressure ◼ Later Part ◼ Fluid move IN – lower hydrostatic pressure ◼ Increased oncotic pressure 33 edema 34 Edema ◼ Buildup of fluid in interstitial space ◼ Major cause ◼ Decreased venous return due to decreased Cardiac Output If only right sided failure Lower extremity edema If left sided failure Pulmonary edema Major cause of right sided failure is left sided failure 35 Edema ◼ Treatment ◼ Diuretic to decrease overall volume Furosemide (Lasix) causes sodium and water loss through kidney ◼ Improve cardiac output Decrease afterload Increase contractility ◼ Other medications – SGLT2 inhibitors for heart failure 36 Lymph System ◼ Most fluid returns to circulation in the capillaries ◼ 10-20% fluid moves to Lymphatic System ◼ Proteins that moved out into interstitium can return via Lymph and thoracic duct into vena cava ◼ Lymph has very low flow rate compared to cardiac output (0.5%) 37 Edema ◼ Other cause ◼ Lymph obstruction Shows importance of lymph in recirculating interstitial fluid Example – elephantiasis Nematode parasite (filariasis) obstructs lymph 38 Moving Cells Out of Vasculature 39 Leukocyte Trafficking ◼ Adhesion – “Rolling” ◼ Through various adhesion molecules on endothelial surface ◼ Some rolling is normal ◼ Increased by inflammation ◼ Firm Adhesion ◼ Some ”crawling” ◼ Flatten “splatting” ◼ Most at sites of inflammation ◼ Diapedesis ◼ Moving through endothelium ◼ Paracellular or Transcellular 40 Where does this occur? ◼ Post capillary - High endothelial ◼ False color EM (cuboidal) venule (most) ◼ Normal trafficking 41 Regulating Blood Flow 42 Systemic Blood Flow - Pressure 43 Determinants of Systemic BP 1. Central factors Heart rate Mostly autonomic regulation MAP = CO x TPR Cardiac output Venous return - Preload Blood volume - hormonal control Renin-Angiotensin-Aldosterone System SV x HR Systemic blood pressure (afterload) 2. Peripheral factors – pertaining to blood and blood vessels Peripheral resistance - R Velocity of blood flow Changes local factors R = 8L / r4 Elasticity of blood vessels Intrinsic property of vessel Viscosity of blood -  eta Diameter of blood vessels - r Length of vessel - L 44 Local Control Blood Flow 1. Autoregulation 2. Tissue Demand 45  Blood Flow affects vasodilation ◼ Coated in Endothelium Surface of vessel ◼ Critical to vessel function and regulation ◼ Produced Nitric Oxide (NO) ◼ Endothelial NO synthase (eNOS) Stimulated by Flow  shear stress Acetyl choline Leukocyte adhesion Chemical messengers bradykinin  Platelet adhesion receptor ◼ NO diffuses into blood Shear Force Decreases leukocyte adhesion Ca++ Decreases platelet adhesion L-arg eNOS NO L-arg eNOS ENDO NO ◼ NO diffuses to smooth muscle cell (SMC) Stimulates Guanylate cyclase to produce cGMP Relaxes SMC Vasodilator Guanylate GTP SMC NO Cyclase relaxation cGMP Therefore, increased flow → ↑shear stress → ↑NO → dilation Relaxation → Vasodilation 46 Mechanisms regulating local blood flow ◼ Metabolic ◼ Metabolism of the tissue produces factors that alter blood flow Particularly increased CO2 and decreased O2 vasodilation or constriction ◼ Endothelial ◼ Particulary NO and PGI2 - Act as vasodilators ◼ PGI2 inhibits platelet aggregation ◼ Myogenic Myogenic Afferent arteriole stretch ◼ Stretch of vessel induces contraction response Stretch activated calcium channel ◼ Renal Specific ◼ Tubuloglomerular feedback Increases intracellular calcium Increased constriction 47 Tissues have different degrees of Autoregulation ◼ High Autoregulation ◼ Autoregulation = Ability to keep ◼ Renal blood flow perfusion constant with changing ◼ Cerebral blood flow blood pressure ◼ Coronary blood flow – maintains flow despite stenotic arteries ◼ Some Autoregulation ◼ Skeletal muscle ◼ Splanchnic – visceral e.g intestines, liver ◼ Little Autoregulation ◼ skin 48 Cerebral autoregulation curve ◼ Between mean arterial pressures (MAP) 50–150 mmHg, cerebral blood flow (CBF) EDEMA remains constant via vasoconstriction or vasodilation ◼ At the extremes, however, compensatory mechanisms fail leading to cerebral ischemia or vasogenic edema ◼ Mechanisms ◼ Myogenic – generally thought most important ◼ Metabolism particularly CO2 ◼ Endothelial realease of NO PGI2 ◼ Neuronal periadvential nerves 49  Need for Autoregulation (of GFR and RBF) ❖ Production of waste remains relative constant ❖ Despite the frequent changes in BP it is important to maintain RBF and GFR relatively constant RBF – Renal Blood Flow GFR – Glomerular Filtration Rate MORE ABOUT THIS IN RENAL Mechanisms of Autoregulation: JG Apparatus Two major mechanisms – Majority of effect is on AFFERENT ARTERIOLE (although not all) Myogenic Afferent arteriole stretch Myogenic There is a direct stretch mechanism in the afferent arteriole so that greater systemic pressure leads to Stretch activated calcium channel increased constriction, thus preventing increase in glomerular pressure that would otherwise have occurred. Increases intracellular calcium Acts through stretch activated calcium channel (Also causes decreased renin secretion) Increased constriction Tubuloglomerular feedback – Increased GFR Increases in GFR lead to increased sodium delivery to Tubuloglomerular feedback the macula densa Extraglomerular Increased NaCl K is pumped into cell (basolateral Cl- Macula Densa Mesangial Cells Afferent Arteriole channel leads to depolarization) Adenosine and ATP release (extracellular ATP is likely converted to adenosine) NKCC2 A1 Adenosine receptors on extraglomerular mesangial 2Cl - Na+ Cl - cells cause increased intracellular Ca++ K + Ca2+ Ca2+ Transmission of Ca++ signal to aff arteriole and Adenosine ATP constriction (Also causes decreased renin secretion) NaCl Ca2+ Delivery CONTRACTION MORE ABOUT THIS IN RENAL GFR Renin Mechanisms of Autoregulation: JG Apparatus Tubuloglomerular feedback – Decreased GFR Decrease sin GFR lead to decreased sodium delivery to the macula densa Decreased NaCl K is pumped into cell this lessens the ATP/adenosine signal leading to Tubuloglomerular feedback - hypovolemia less constriction of afferent arteriole If more severe hypovolemia, then other Macula Densa Afferent Arteriole mechanisms can come into play increased COX2 activity EP4 increased PGE2 Na+ NKCC2 - PGE receptors on extraglomerular mesangial cells - Cl CONTRACTION 2Cl + EFFERENT > AFFERENT K Ca2+ cause decreased intracellular Ca++ at afferent COX arteriole causing dilation and help maintain GFR PGE2 PGE2 (Also causes increases renin secretion) NaCl because of the hypovolemia and increased renin Delivery ANG-II secretion RELAXATION ang-II is elevated GFR Renin causes overall systemic vasoconstriction to maintain BP causes afferent a. constriction but less than efferent a. so decreased RBF but maintains GFR better than it would have otherwise MORE ABOUT THIS IN RENAL Tissue Activity Regulating Local Blood Flow ◼ Blood Flow ◼ Increased blood flow can lead to vasodilation ◼ Decreases resistance to maintain more constant BP ◼ Metabolism of Tissue ◼ Particularly important in exercise to increase blood flow to muscles 53 Different regulation in different vascular beds help distribute blood flow during exercise Brain – autoregulated - actually controversial if increases, EXCERCISE depends on the method used REST Heart – mostly metabolic regulation ↓ATP → K+ release →vasodilation Skeletal Muscle – highly regulated by demand Mostly metabolic ↓ATP → adenosine, NO, CO2, H+ →vasodilation Skin– Not autoregulated Regulated by thermoregulation Vasodilation mainly regulated by cholinergic sympathetic nerves Renal – autoregulated – some debate about if decreases significantly. No difference if immediately after exercise 54 Changes in Blood Flow Distribution with Exercise CO 5x increase ◼ Brain – no change ◼ Heart – increase 4x-5x ◼ mostly metabolic regulation ◼ ↓ATP → K+ release →vasodilation ◼ Visceral – decrease ◼ Renal – no change ◼ Skeletal Muscle – large increase 20x-25x ◼ Mostly metabolic ◼ ↓ATP → adenosine, NO, CO2, H+ →vasodilation Multisystem physiological perspective of human frailty and its modulation by physical activity Joseph A. Taylor, Paul L. Greenhaff, Davi d B. Bartlett, Thomas A. Jackson, 27 JAN 2023https://doi.org/10.1152/physrev.00037.2021 55 Vascular Diseases ◼ Atherosclerosis ◼ PAD ◼ AAA ◼ Ascending aortic aneurysm (dissection) ◼ Stroke 56 Atherosclerosis – THE BIG ONE ◼ Buildup of lipids in intimal cells (foam cells) ◼ Can be prone to rupture (clot and acute thrombus) ◼ Plaque has inflammation, fibrosis, immune cell infiltration ◼ Can also give severe fixed obstruction 57 Atherosclerosis – major vascular disease ◼ Buildup of lipids in vessels Aortic wall of 62-year-old man. Fibrous intimal thickening, within normal ◼ Inflammation range (van Gieson elastic stain). ◼ Changes in architecture of vessel ◼ Cause of coronary artery disease and MI ◼ thickening of the arterial tunica intima (fibrosis) Fragmentation of ◼ fragmentation of the elastic layers. the elastic layers in a temporal artery (van Gieson elastic stain) 58 Peripheral Arterial Disease (PAD) Highly associated with atherosclerosis 59 Risk Factors for PAD Reduced Increased Smoking Diabetes Hypertension Hypercholesterolemia Hyperhomocysteinemia C-Reactive Protein Relative Risk 0 1 2 3 4 5 6 Hirsch AT, et al. J Am Coll Cardiol. 2006;47:e1-e192. 60 PAD Symptoms ◼ Claudication Classic Symptom Triad ◼ Muscle-based pain, heaviness, ache ◼ Provoked by exertion (walking) ◼ Relieved with rest ◼ Rest Pain ◼ Not Muscle-based ◼ At extremes of circulation (heel, ball of foot) ◼ Nocturnal 61 Computed Tomographic Angiography (CTA) ◼ Requires iodinated contrast ◼ Requires ionizing radiation ◼ Produces an excellent arterial picture 62 Magnetic Resonance Angiography (MRA) ◼ Excellent arterial picture ◼ No ionizing radiation ◼ Gadolinium use in individuals with an eGFR 5.5 cm ◼ Mean follow-up 4.9 years 65 AAA: Surgical Repair 66 Aortic Dissection ◼ Separation of layers of aorta ◼ Can be confused with MI ◼ Life threatening emergency Stanford type A Stanford type B Involves the ascending aorta Confined to descending aorta with or without descending aorta Treasure T, et al. J Heart Valve Dis 1996;5:623-29. 67 Stroke 68 Stroke ◼ Strokes can occur from emboli ◼ Carotid disease ◼ Cardiac disease (atrial fibrillation) ◼ Remember anatomy of cerebral vessels 69 The End 70