Endothelial_cell_function_and_dysfunction-Oct_25th_2023.pptx

Endothelial cell function and dysfunction Pedro Del Corral, Ph.D. M.D. Associate Professor Department of Physiology & Pathology Burrell College of Osteopathic Medicine October 25th 2023 1 Objectives: Robins & Cottran (121, 483-487; Guyton Medical Physiology: Ch 16: 189, Ch 17: 208-209; Ch 37: 48...

Endothelial cell function and dysfunction Pedro Del Corral, Ph.D. M.D. Associate Professor Department of Physiology & Pathology Burrell College of Osteopathic Medicine October 25th 2023 1 Objectives: Robins & Cottran (121, 483-487; Guyton Medical Physiology: Ch 16: 189, Ch 17: 208-209; Ch 37: 489) • Describe the key features of the vascular endothelium • List the differences in structure and permeability between the three types of endothelium • List the steps that allow for leukocyte movement across endothelium. • Diagram the synthetic pathway for nitric oxide • Compare and contrast the basal and activated state of the endothelium • Describe the function of active compounds synthesize by the endothelium • Describe the role of oxidative stress in endothelial dysfunction • Describe the role of endothelium function in atherosclerosis 2 Vascular structure & function 483-485 Figure 11-1 Regional specializations of the vasculature. The aorta has substantial elastic tissue to accommodate high pulsatile forces, with the capacity to recoil and transmit energy into forward blood flow. The muscular arteries and arterioles have concentric rings of medial smooth muscle cells whose contractile state regulates vessel caliber and, thereby, blood flow and blood pressure. The venous system has relatively poorly developed medial layers that permit greater capacitance. The capillary wall is comprised only of an endothelial cell and sparse encircling pericytes. Loss of aortic elastic tissue in a large artery may result in aneurysm, while stasis in a dilated venous bed may produce a thrombus. 3 Vascular structure & function 483-485 (new figure) • Arteries, lymphatics, veins • Vascular wall constituents: • Endothelium, smooth muscle • Extracellular matrix • Elastin, collagen, glycosaminoglicans • Specific composition/location → susceptibility to injury/disease • Disease associations • Atherosclerosis -Elastic & muscular arteries • HTN- Small muscular arteries & arterioles • Vasculitis-Depend on type 4 The endothelium is the physical separation between blood and tissue A. This schematic drawing shows the luminal surface of the endothelium. The cells are elongated with their long axis parallel to the direction of blood flow. Nuclei of endothelial cells are also elongated in the direction of blood flow. Contact with blood flow B. Scanning electron micrograph of a small vein, showing the cells of the endothelial lining. Note the spindle shape with the long axis of the cells running parallel to the vessel. 5 Endothelial cells form a specialized lining for blood vessels • There are differences among the different segments of the vascular tree • Morphological differences • Differences in gene expression • Large vessels vs capillaries • Arteries vs veins • Location: • Brain • BBB properties are primarily determined by tight junctional complexes between the cerebral endothelial cells. • Water, O2, CO2 • Liver • Cleft between capillary endothelial cells are wide Type of endothelial cell linings 6 The endothelium is phenotypically heterogeneous Caveolae, intercellular clefts Lung/Heart---------------------------------------Glomerulus-------------------------------------Liver Functions… 7 Endothelial cell functions: • 1. Maintain selective permeability barriers • • • • Simple diffusion Active Transport Pinocytosis Receptor mediated endocytosis 8 Endothelial cell functions: • 2. Have a nonthrombogenic surface that maintain the blood in a fluid state • Balance between procougulant and anticoagulant • Prevent thrombosis • Limit clotting to sites of vascular damage • Tissue factor • However, inflammation can tip the balance  weak antithrombotic properties • Platelets • Coagulation factors • Fibrinolysis Continue 9 Endothelial cell functions: Maintains a nonthrombogenic surface • Platelet inhibition, the endothelium • Shields from interaction: vWF & collagen • ↓ Activation & aggregation • PGI2, ADPase, & NO • Anticoagulation • Heparin like molecules • Thrombomodulin • Fibrinolysis • tPA 10 Damaged endothelium is prone to thrombus formation Endothelial Irritants? Fate of thrombus Types of blood flow Endothelial cell functions: • 3. The endothelium modulates blood flow and vascular resistance • Mediates medial smooth muscle cell tone • T ½ of NO relevance • Achieved by the secretion of vasoconstrictors (endothelins, angiotensin-converting enzyme [ACE], prostaglandin H2, thromboxane A2) and vasodilators (nitrous oxide [NO], prostacyclin). 12 Endothelial NOS is the key regulator of vascular tone • ROS • Superoxide • Reduces BH4 • eNOS ability to produce NO • Hyperglycemia stim ROS • Inflammation stim ROS Vascular permeability 13 Vascular injury 14 Endothelial cell damage increases vascular permeability------------------Inflammation • Leucocyte extravasation steps: • Margination & rolling • Selectins • Tight bindings - Adhesion • ICAM & VCAM • Diapedesis • PECAM • Migration • Chemotactic signals 15 Vascular injury: Endothelial cells adjust their steady state function & by expressing newly acquired properties –Collectively known as endothelial activation • Endothelial cells • Heterogeneous: liver vs Brain • Gene expression • NO, ET-1 • Smooth muscle tone/growth • Smooth muscle • Proliferation, synthesis, tone • Vascular repair, atherosclerosis • Vascular injury (endothelial): • ↑Smooth ms migration, proliferation, extracellular matrix synthesis • Intimal thickening • Regulated by cytokines, growth factors from: • Endothelium, platelets, macrophages, complement • Result variable stenosis 16 Figure 11-2 Basal and activated endothelial cell states. • Normal blood pressure, laminar flow, and low growth factor levels promote a basal endothelial cell state that maintains a nonthrombotic, nonadhesive surface with appropriate vascular wall smooth muscle tone. • Smoothness of endothelial cells:↓ clotting • Glycocalyx on endothelial cells: ↓ clotting & platelet • Thrombomodulin: ↓ clotting • Injury or exposure to certain mediators results in endothelial activation, a state where endothelial cells develop a procoagulant surface that can be adhesive for inflammatory cells, and also express factors that cause smooth muscle contraction and/or proliferation and matrix synthesis. • Endothelial damage • ↓in smoothness, glycocalyx, thrombomodulin: • ↑ clotting (activates factor XII, platelets) 17 Endothelial dysfunction: a window into atherosclerosis Modification of the lipoproteins occurs by oxidation. Lipoproteins, mainly LDLs with a high cholesterol content and very low-density lipoproteins (VLDLs), are oxidized by free radicals produced by endothelial cells. Modified LDLs, in turn, are rapidly endocytosed by macrophages to form foam cells. Foam cells are a characteristic feature in the formation of atheromatous plaques. 18 Clinical Physiology • Effects of atherosclerosis & hypertension on the endothelial cells • Clinical Relevance? • CAD • ED • Pulmonary-HTN • ET-1 antagonists 19 Clinical Physiology: How do we assess endothelial function In Vivo? • Whose endothelial dysfunction? • What can we do about it 20