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Endothelial cell in health & disease seminar

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Endothelial cell in health & disease seminar

  1. 1. ROLE OF ENDOTHELIAL CELL IN HEALTH & DISEASE SWEETY KALANTRI
  2. 2. Simple Squamous epithelium (monolayer) Thinnest possible type of membrane
  3. 3.  Endothelium is thin layer of cells which lies the interior surface of blood vessels and lymphatic vessels  Cells which form endothelium are called endothelial cells (EC’s)  Mesodermal in origin  It forms an interface between circulating blood/lymph in the lumen and rest of the vessel wall  Most quiescent & genetically stable cells of the body- turnover time usually 100 days
  4. 4. HISTORY  Endothelium- 1st described by Virchow in capillaries as a simple membrane with flattened nuclei  Swiss Anatomist Wilhelm His- introduced the term “endothelium”  Waldayer -suggested the term restricting to those cells that make up the innermost layer of blood vessels and lymph vessels & posterior lining of cornea  1st pro-angiogenic factor (bFGF)- purified in 1984 from tumor cells by Sching & Klagsbrun
  5. 5. The vascular wallThe vascular wall
  6. 6. Endothelial cells Liver /Sinusoidal
  7. 7. EMBRYOGENESIS
  8. 8.  Earliest blood vessels develop from Blood islands (insulae sanguineae) which appear in mesoderm surrounding the wall of the yolk sac at 3 weeks of development
  9. 9. Centre of blood islands form Hematopoeitic stem cells ( Precursor of all blood cells) Peripheral hemangioblasts form Mesodermal cells HEMANGIOBLAST ANGIOBLAST(Precursor of blood vessels FGF- 2 VEGF
  10. 10.  Angioblasts proliferate and eventually induced to form EC’s (by VEGF, secreted by surrounding mesoderm cells)  Once process of vasculogenesis estalishes a primary vascular bed, additional vasculature is added by angiogenesis, the sprouting of new vessels (by VEGF)  Maturation & modeling of the vasculature is regulated by other GF’s ( PDGF, TGF-b )
  11. 11. VEGF- A
  12. 12. VEGF  Signalling protein- Mediates both vasculogenesis & angiogenesis  Stimulates-- EC mitogenesis EC migration Enhances microvascular permeability (aka Vascular permeabilty factor VEGF VEGFR’s( tyrosine kinase receptors )- present on cell surface
  13. 13. VEGFR-2/ Flk 1/KDR Mediates lymphangiogenesis
  14. 14. VEGF Receptor KDR ( kinase insert domain receptor 2)- It is human gene encoding Flk-1 VEGFR-2 KDR is designated as CD 309 Flk -1 (fetal liver kinase 1)
  15. 15.  Expression of flk-1 represents the earliest marker of the developing endothelial lineage during vasculogenesis  SCL (Stem cell leukaemia) transcription factor/ TAL- 1 i.e T-cell acute lymphocytic leukaemia= crucial for the development of blood cells and blood vessels  AC 133 / / Prominin - 1= Useful marker for isolation of hematopoeitic & endothelial progenitor cell  (homeobox gene)- marker for both hemangioblast and angioblast present only in endothelial precursors flk-1 SCL CD 133 Hex
  16. 16. CD133 is absent on mature endothelial cells and monocytic cells
  17. 17. Microvasculature (Capillaries & post capillary venules EC’s Pericytes • Contractile function • Multipotential capabilities- differentiate to adipocytes, osteoblasts, phagocytes, SMC’s • Pericytes & SMC’s recruit to form periendothelial layer- for vessel maturation & stabilisation • Imp for BBB formation / Mural /Rouget cells
  18. 18. STRUCTURE  Epithelial lining of the vascular system  Almost always Simple squamous epithelium  EC’s are very flat and elongate, have central nucleus, thickness is maximum at the level of nucleus(2-3 µm), 10-20 µm in diameter  Elsewhere-thinner and laminar; in capillaries as thin as 0.2 µm  Elongated in the direction of the blood flow, especially in arteries
  19. 19.  Cytoplasm is relatively simple with few organelles; mostly concentrated in the perinuclear zone  At ultra structural level, they have few characteristic organelle e.g.1) transcytotic/ pinocytotic vesicle 2) caveole 3) Weibel-Palade body
  20. 20. TRANSCYTOTIC VESICLE : - in all ECs but particularly present in exchange vessels - shuttle small amount of extracellular fluid or blood plasma across the endothelial cytoplasm -facilitates bulk exchange of dissolved gases, metabolites and nutrients -E.g. in the lung capillaries where there is very efficient movement of gases (carbon dioxide, oxygen and anaesthetics etc) .
  21. 21. CAVEOLE : - special type of transcytotic vesicle - typical in vessels of smooth muscle cells - vesicular invagination of cell surface - associated with receptors, enzymes and ion channels
  22. 22. WEIBEL-PALADE BODY : -also known as rod-shaped (micro) tubulated bodies -characterizes EC’s - elongated cytoplasmic vesicle(3 x 0.1) µm single membrane; dense interior, -stores adhesion molecule, P- selectin Von Willebrand factor( vWF )
  23. 23. INTERCELLULAR JUNCTION BETWEEN ADJACENT EC’s Syndesmos
  24. 24.  Formed by Cadherin- trans membrane gp  Cell to cell contact & with cytoskeleton  Cadherin 5/ VE cadherin/ Endothelial specific cadherin
  25. 25.  In large arteries & brain vessels  Composed of- Occludin, Claudin 5, JAM’s( Junctional adhesion molecules  Present more at the apical region of the cell  Function-Seals neighboring cells together to prevent leakage of molecules between them
  26. 26.  c/o Connexons- mainly of 37, 40, 43 (detected in EC’s)  Function-cell to cell junction allowing passage of small water soluble ions & molecules
  27. 27. ENDOTHELIAL HETEROGEINITY  EC’s exhibit different phenotype- both in structure & function  heterogeneity is linked to both intrinsic, i.e., genetic factor, and extrinsic factors  Structural heterogeneity- obtained following electron microscopy observations where differences in intercellular junctions led to the classification of- # continuous endothelium # fenestrated endothelium # discontinuous endothelium
  28. 28. Endocrine glands, GI mucosa Glomerulus Liver Spleen BM
  29. 29.  Specialized EC’s of post capillary venules  plump cuboidal morphology, have large no. of lymphocytes within their walls, basal lamina is continuous, 7-30µm A) High Endothelial Venules (HEV)-  HEVs are found in all secondary lymphoid organs except spleen  HEVs enable lymphocytes to move in and out of the lymph nodes from the circulatory system HEV-expresses addressins (specific adhesion molecules) eg CD34 Mad CAM1 Attaches to L-selectin on Lymphocytes
  30. 30. BLOOD BRAIN BARRIER:BBB-  It is highly selective permeability barrier that prevent the entry of lipid insoluble substances to enter brain, SC & peripheral nerve  BBB is formed by capillary EC’s which are connected by tight junctions & relative lack of transcytotic vesicle  Tightness of barrier depends upon the close apposition of astrocytes (astrocyte cell projections surround the EC’s of BBB)  Circumventricular organs lack it.
  31. 31. LUNG :  respiratory membrane  have a selective phagocytic activity & are able to extract substances from blood KIDNEY :  finely fenestrated : functions as a selective filter  Principle barrier(≈33µm)--is the BM, the fused endothelium & podocyte basal lamina  And allows the passage of water, small molecules & ions; but not larger & those with -ve charge
  32. 32. /PECAM-1 Receptor for TGF-b /CD105
  33. 33.  7B4 antigen  ACE (angiotensin-converting enzyme)- endothelial enzyme  BNH9/BNF13  CD31(PECAM-1)  CD34 (Gly CAM 1)  CD54 (ICAM-1)  CD106 (VCAM-1)  CD62P (p-Selectin GMP140)  CD105 (Endoglin)  CD146 (P1H12)  E-selectin  Endothelial cell autoantibodies  Endoglyx-1 FEW MARKERS
  34. 34.  Endosialin (tumor endothelial marker 1, TEM-1, FB5)  (VEGFR-1)  ICAM-2 (intercellular adhesion molecule 2)  Thrombomodulin (TM, CD141)  VEGF (Vascular endothelial growth factor)  vWF (von Willebrand factor)
  35. 35. CLINICAL ASSESSMENT OF ENDOTHELIAL FUNCTION  by both invasively and non- invasively  involves evaluating measure of endothelial cell behavior in vivo viz endothelium dependent vasodilatation  done using either pharmacological or mechanical agonist that stimulates endothelium to release effector molecules that alter underlying SM cell tone.
  36. 36. INVASIVE PROCEDURE :  agonist that stimulate release of endothelial NO is used e.g. acetyl choline & methacholine (short lived rapidly acting )  intracoronary infusion is given  Change in coronary diameter is measured
  37. 37. NON- INVASIVE PROCEDURE :  Assessed in the forearm circulation  Brachial artery blood flow is occluded with a BP cuff  Then cuff is deflated  change in blood flow and diameter is measured ultrasonographically  depends upon - -shear stress-dependent changes in endothelial release of NO following restoration of blood flow & -the effect of transient adenosine released from ischemic tissue.
  38. 38. RESULTS:  Normally the change is approx. 10%  Endothelial dysfunction( ED) is defined by- smaller change & in extreme cases ,a paradoxical vasoconstriction effect is also seen.  Occurs due to direct effect of cholinergic agonist on vascular SMC  ED seen in pat with atherosclerosis & risk factors(HTN, ↑cholesterolemia, DM, smoking etc.)
  39. 39. PERMEABILITY BARRIER & TRANSPORT  provide barrier between the blood and rest of the body tissues  Simple diffusion- O2, CO2  Active transport- Glucose, AA’s, electrolytes  Pinocytosis- small molecules, soluble proteins  Receptor mediated endocytosis (clathrin dependent process)- GF’s, Antibodies, LDL, Transferrin, MHC complexes
  40. 40. SYNTHESIS OF-  Role in VASOMOTION- 1. Prostacyclin (PGI2) 2. Endothelium derived hyperpolarizing factor( EDHF) 3. Nitric oxide (NO)/ (EDRF) Vasodilator factors 1. Endothelin-1 2. Thromboxane (TXA2) 3. Angiotensin II Vasoconstrictive factors NOS 3 subtype present in EC’s
  41. 41.  Secretes ECM protein- 1. Basal lamina- collagen, laminin, elastin, fibronectin 2. Glycocalyx - Proteoglycans • Smoothness of endothelial surface- due to glycocalyx • Negative charge on EC’s – due to GAG’s (mainly heparan SO4) (EC’s binds to ECM via Integrin)  Secretion of growth stimulating factors-PDGF, FGF, GM- CSF  Secretion of growth inhibiting factors- heparin, TGF- β  Secretion of IL-1, IL-6, IL-8
  42. 42. PECAM 1 (CD31)-  found on the surface of endothelial cell intercellular junctions, platelets, monocytes, neutrophils, macrophages, lymphocytes, megakaryocytes  involved in leukocyte transmigration, angiogenesis & integrin activation VCAM-1 (CD106)-  expressed on both large and small blood vessels only after EC’s are stimulated by cytokines  mediates the adhesion of lymphocytes, monocytes, eosinophil, and basophils to vascular endothelium  Major BM addressin for hematopoeitic progenitor cells expressing VLA-4 / integrin α4β4
  43. 43. ICAM (CD54)-  is expressed by the vascular endothelium, macrophages, and lymphocytes.  is a ligand for LFA-1 (integrin) , a receptor found on leukocytes.  stabilizing cell-cell interactions and facilitating leukocyte endothelial transmigration
  44. 44. HEMOSTATIC FUNCTIONS- Intact endothelium Homeostatic Phenotype Damaged endothelium Dysfunctional phenotype
  45. 45.  Anticoagulants- production of Thrombomodulin (CD141)- (co-factor for thrombin)  Anti thrombogenic agents- production of prostacyclin, heparin, t PA, anti thrombin III  Pro thrombogenic agents( released after damage to cells)- # tissue thromboplastin, vWF, PAI Clotting Role in CLOTTING-
  46. 46. Role of EC in normal hemostasis
  47. 47. INFLAMMATION  Leucocyte normally repelled by endothelium(for free flow of blood )  Inflammatory states - leucocytes are attracted to the endothelium by leucocyte adhesion molecules( expressed on EC’s)- leucocyte Margination  They leucocyte pass by diapedesis  Hallmark of inflammation- Increased vascular permeability → edema  Vascular leakage occurs due to contraction of EC (M.C.)
  48. 48. ENDOTHELIUM AS AN ORGAN  1-2 trillion EC’s, forming an almost 1.5 kgs organ  Uniquely contains Weibel-palade bodies (stores vWF)  Not only a permeability barrier, also multifunctional paracrine & endocrine organ  Involved in- immune response, growth regulation, coagulation production of extracellular matrix components modulator of blood flow & blood vessel tone
  49. 49. ROLE IN DISEASE  Oxidative Stress leads to Endothelial dysfunction (ED)  ED- 1) decreased NO 2) increased Endothelin ( ET-1 binds to Endothelin A and B receptors in pulmonary vascular bed- potent vasoconstrictor)  It is also a physiological process  Takes place gradually by age and menopause.
  50. 50. ENDOTHELIUM IN CVS DISEASE
  51. 51.  Disease of large & medium sized muscular arteries  Characterized by- 1. ED 2. vascular inflammation 3. Atheroma's/atherosclerotic plaque--build up of cholesterol, lipids, cellular debris, calcium & fibrin within the intima.intima
  52. 52.  Angiotensin-converting-enzyme(ACE) is an endothelial enzyme  Converts angiotensinogen I to angiotensinogen II  A II is a potent vasoconstrictor: important in pathogenesis of hypertension Hypertension
  53. 53. SMOKING  Nicotine- opens up intercellular junction & allow large molecules to pass through the wall  Such toxins can potentiate degenerative changes in the blood vessels & lead to vascular disease  Prolonged( years ) smoking of one pack of cigarettes daily or more –daily, increase death rate from IHD by 200%  Smoking cessation decreases that risk substantially
  54. 54. ENDOTHELIUM & STROKE  Production of EDCF- counteracts the normal dilator effect of NO  Reduced activity of NO synthase  Presence of Hemoglobin in SAH- # inhibition of NO- vasospasm
  55. 55. DIABETES
  56. 56.  ENDOTHELIUM & CKD
  57. 57. ENDOTHELIUM & SEPSIS
  58. 58.  TTP & HUS are caused by insult that activates platelets & deposited as thrombi in microcirculation  Superimposition of endothelial injury may further promote platelet micro aggregate formation : initiate or exacerbate Thrombotic microangiopathies
  59. 59. PHYSIOLOGICAL ANGIOGENESIS
  60. 60. TUMOR ANGIOGENESIS
  61. 61.  In disease , EC growth supports metabolic requirement of tumor beyond few mm : growth of primary & metastatic tumor  Several steps= -stimulation of EC -degradation of ECM -proliferation of EC & migration into tumor -Formation of new capillary tubes  Tumor vessels are= -tortuous -dilated, uneven diameter -excessive branching &shunting -lack perivascular cells
  62. 62. ANTIANGIOGENIC THERAPY  Acquired drug résistance of tumor – due to high intrinsic mutation rate -- major cause of treatment failure  But ECs are genetically stable ; ECs apoptosis pathway is intact  EC provides nourishment to many tumor cells; tumor growth dependent on angiogenesis  blockade of a single GF (e.g. VEGF) may inhibit tumor induced vascular growth
  63. 63. von Willebrand disease  vWF required for interaction & adhesion of platelets to ECM  Genetic absence of this factor( AD, rare AR)→von Willebrand disease
  64. 64.  The WHO classification of vascular tumors A)Benign= 1) Hemangiomas -sub cut/deep -capillary -cavernous -arteriovenous -Venous -intramuscular -synovial 2) Epitheloid Hemangiomas 3) Angiomatosis 4) Lymphangioma TUMOR OF ENDOTHELIAL CELLS
  65. 65. B) Intermediate (locally aggressive) -Kaposiform hemangioendothelioma C) Intermediate (rarely metastasizing) -retiform hemangioendothelioma -papillary intralymphatic angioendothelioma -composite hemangioendothelioma -kaposi sarcoma D) Malignant -Epitheloid hemangioendothelioma -Angiosarcoma of soft tissue
  66. 66.  EC’s play a vital role in health and integrity of every tissue of the body because apart from cartilage, every cell lies within a few µm of a capillary  The diffusion limit of oxygen in tissue is only ≈ 100µm,and can not cross blood vessel thicker than that  fine capillaries ( 10-15 µm ) & consist merely of endothelial cells and a very fine basal lamina, thus helps in providing oxygen, nutrients & metabolites. Summary
  67. 67.  adjust their number & arrangement to accommodate local requirement  Thus, they are life-support tissue extending & remodeling the network of blood vessels to enable tissue growth, motion & repair.  Dysfunction of EC has been implicated in virtually every type vascular disease( Atherosclerosis,HTN etc.)  and hence integrity & proper function of EC is essential for proper organ function and good health.
  68. 68.  Pathological basis of disease : Robbins & Cotran,8th e  Harrison’s internal medicine: 17th e  WHO classification: tumors of soft tissue and bone  Hematology : Basic Principles & Practise,5th e( Hoffman)  Hemostasis and Thrombosis –Basic Principles & Practice, 5th e( Colman , Goldhaber )  Internet sites References
  69. 69. THANK YOU

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