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Biochemistry of Endothelial Cells

Biochemistry of Endothelial Cells. Doc. Dr. Mine KUCUR. ENDOTHELIUM. Provides a cellular lining to all blood vessels in the circulatory system and forms a structural barrier between the vascular space and the tissue.

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Biochemistry of Endothelial Cells

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  1. Biochemistry of Endothelial Cells Doc. Dr. Mine KUCUR

  2. ENDOTHELIUM • Provides a cellular lining to all blood vessels in the circulatory system and forms a structural barrier between the vascular space and the tissue. • In adults, the endothelium weights approximately 1kg, comprises 1.6x1013 cells and has a surface area between 1-7 m2. • Each EC comes into contact with numerous smooth cells.

  3. Tunica intima LUMEN Tunica adventitia Tunica media

  4. Note the individual Endothelial Cells

  5. Vasoconstriction and dilatation Normal Vasoconstriction Vasodilatation

  6. Vasoconstriction and dilatation ↓Resistance to flow ↑ Resistance to flow Vasodilatation Vasoconstriction

  7. Endothelial Apoptosis Apoptosed Normal

  8. The EndotheliumAs an Endocrine Organ

  9. The Vascular Endothelium • The inner lining of our bloods vessels is the Endothelium • It plays a central role in regulating the vasomotor tone (vasoregulation) • Local homeostasis & control of the coagulation process (provision of anti-thrombotic surface and selective permeability to haematopoietic cells and nutrients) • Endothelial cells have ‘Sensors’ and release ‘Mediators’ • ‘Mediators’ are the functional molecules on the cell surface

  10. Vascular Endothelial Mediators Include the following • Nitric oxide (NO) • Cycloxygenase (CxO) • Endothelin-1 (ET-1) • Endothelium Depolarisation Factor (EDF) • And many others - thus • It is the largest endocrine gland

  11. Nitric Oxide (NO) • NO is generated in ECs by the oxidation of L-arginine to L-citrulline by a family of enzumes, NO synthases (NOS) • Half-life of NO, is affected by its chemical reaction and inactivation by superoxide anion • NO is the most abundant free-radical in the body • It is the only biological molecule in high concentrations to out-compete superoxide dismutase for superoxide • NO has an anti-thrombogenic & anti-atherogenic role

  12. Protective actions of NO Endothelial NO has the following actions • Smooth muscle relaxation and vasodilatation- maintenance of basal vasomotor tone • Essential for regulation of blood pressure • Reduces proliferation of vascular smooth muscle • Protects blood vessel intima from injurious consequences of platelet aggregation-inhibition of thrombosis by inhibiting platelet adhesion, activation and agonist-inducedsecretion.

  13. (L-NMMA) = N(G)-mono-methyl-L-arginine

  14. ED and NO ↓ NO deficiency in the vessel wall promotes • Inflammation • Oxidation of lipoproteins • Smooth muscle proliferation • Accumulation of lipid rich material • Platelet activation and thrombus formation Finally results in atherosclerosis.

  15. Endothelins • A family of 21 amino acid peptides. • Three members: ET-1,ET-2 and ET-3. • Regulate vasomotor tone, cellular proliferation and hormone production. • ECs produce only ET-1, also syntesized by vascular smooth cells. • Production is induced by hypoxia, ischemia. • ET-1 binds to specific receptors on smooth cells: vasoconstriction.

  16. Endothelins  Disease • Elevated plasma concentrations of ETs are found in congestive cardiac failure. • Plasma ET-1 levels are normal in essential hypertension. • Endothelins have been implicated in vascular diseases of the kidney and cyclosporin induced nephrotoxicity. • Plasma ET levels are elevated after ischaemic cerebral infarction.

  17. Prostacyclin(PGI2) • Eicosanoid. • Synthesis is induced by disturbances in endothelial function or vascular haemodynamics. • Released from ECs and acts in a paracrine manner. • Binds to a specific receptor on platelets and vascular smooth muscle cells to limit vasoconstriction and influence platelet deposition.

  18. Platelet Activating Factor (PAF) • Phospholipid, remains bound to the EC surface. • Most important effect is recruiting leucocytes to the EC surface, and its effects on vascular tone are indirect and exerted through the generation of other eicosanoids and leukotrienes.

  19. ENDOTHELIUM IN INFLAMMATION • Leucocyte transmigration to extravascular sites of inflammation. • Initial step is the arrest of leucocytes and random contact with the ECs. • Mediated by the selectins. • Increasing adhesion occurs with activation of the leucocyte integrins. • Leucocytes flatten and migrate along the endothelium: diapedesis.

  20. ENDOTHELIUM IN INFLAMMATION • Activated endothelium bind leucocytes. • Is activated in response to cytokines including IL-1, TNF- and lipopolysaccharide which expresses adhesion molecules and bind leucocytes.

  21. Selectins • Three members: E-Selectin, L-Selectin and P-Selectin. • Characterized by a C-terminal lectin like domain that binds complex carbohydrates. • Involved in leucocyte recruitment to sites of inflammation.

  22. Integrins • Integrins relevant to leucocyte recruitment are  1 integrins and the  2 integrins. •  1 integrins mediate binding to the ECM (fibronectin and laminin). Binds cell surface VCAM-1. •  2 integrins are present only on leucocytes and their activity depends on conformational changes that occuron leucocyte activation. • Integrin-immunglobulin superfamily interaction is essential for extravasation to occur.

  23. COAGULATION ECs maintain anticogulant activity: • Prevent activation of thrombin- if activated, stimulates coagulation by causing platelet activation and the activation of several coagulation factors. • Express heparan suphate- stimulates antithrombin III. • Express tissue factor pathway inhibitor (TFPI)- prevents thrombin formation.

  24. COAGULATION • Express thrombomodulin. • Thrombomodulin-thrombin interaction activates protein C- strong anticoagulant activity. • Synthesize protein S, a cofactor for activated protein C. THE BALANCE IS TOWARDS ANTICOAGULANT FACTORS IN HEALTHY ENDOTHELIUM !!!

  25. The Endothelium inHealth and Disease

  26. Genes Coronary Risk Factors Endothelial Dysfunction NO ↑ Inflammation ↑ Thrombosis Coronary Heart Disease The Essential Components The Universal Damage

  27. endothelial NOS (eNOS)is induced byreceptor dependent agonists such as thrombin,bradykinin and substance P. • NO causes vascular smooth muscle relaxation bybinding to guanyl cyclase. • plays a critical role in the inhibition of thrombosis by inhibiting platelet adhesion, activation and agonist-induced secretion. • NO promotes platelet desegregation.

  28. Regulatory Functions of the EndotheliumNormal Dysfunction Vasodilation Vasoconstriction NO, PGI2, EDHF, BK, C-NP ROS, ET-1, TxA2, A-II, PGH2 Thrombolysis Thrombosis tPA, Protein C, TF-I, vWF PAI-1, TF-α, Tx-A2 Platelet Disaggregation NO, PGI2 Adhesion Molecules CAMs, P,E Selectins Antiproliferation NO, PGI2, TGF-, Hep Growth Factors ET-1, A-II, PDGF, ILGF, ILs Inflammation ROS, NF-B Lipolysis LPL Vogel R

  29. Clinical Sequelae

  30. Oxidative stress and Endothelial dysfunction • Oxidative Stress leads to ED • Endothelial dysfunction is mainly due to reduced bioavailability and bioactivity of Nitric Oxide (NO) • It is also a physiological process • Takes place gradually by age and menopause.

  31. The Effects of ED • Oxidant stress and Endothelial dysfunction are major factors for atherosclerosis – the common pathway– • for most of the cardiovascular risk factors including Hypertension, DM, Dyslipidemia and Smoking. • Both endothelial dysfunction and oxidant stress result in clinical conditions - Heart failure, IHD and MI

  32. CONCLUSIONS • Advances in the understanding of endothelial function have been the basis for many therapeutic strategies. • Expanding the understanding of endothelial function will lead to targeted therapies to a myriad of diseases such as cancer, cardiovascular disease and inflammatory conditions.

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