Angiogenesis

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Angiogenesis

  1. 2. Presented by : Mr. Nirav S. Vachhani M.Pharm Pharmacology (Sem-1) Guided by : Dr. Rina H. Gokani S. J. Thakkar pharmacy college, Rajkot.
  2. 3. <ul><li>Definition: </li></ul><ul><li>Angiogenesis is a physiological process involving the growth of new blood vessels from pre-existing vessels. </li></ul>Angiogenesis
  3. 4. <ul><li>Introduction: </li></ul><ul><li>Blood vessel formation is of two types Vasculogenesis and Angiogenesis. </li></ul><ul><li>Vasculogenesis is the generation of blood vessels from endothelial cell progenitors (hemangioblasts). It is responsible for the formation of the primary vasculature of the body during early embryonic development. </li></ul><ul><li>Angiogenesis is a physiological process involving the growth of new blood vessels from pre-existing vessels. </li></ul>
  4. 5. <ul><li>Angiogenesis occurs in the healthy body for healing wounds and for restoring blood flow to tissues after injury or insult. </li></ul><ul><li>In females, angiogenesis also occurs during the monthly reproductive cycle (to rebuild the uterus lining, to mature the egg during ovulation) and during pregnancy (to build the placenta, the circulation between mother and fetus). </li></ul>
  5. 6. <ul><li>Angiogenesis is a complex, highly regulated process, involving the sprouting, splitting, and remodeling of the existing vessels. </li></ul><ul><li>Many pathological conditions such as ischemic tissue injury are also benefited by revascularization. </li></ul><ul><li>On the other spectrum, excessive angiogenesis may result in different diseases like cancer, atherosclerosis, rheumatoid arthritis, blindness, etc… </li></ul>
  6. 7. <ul><li>Process of Angiogenesis: </li></ul><ul><li>The vascular network formation consists of multiple coordinated, sequential, and interdependent steps mediated by a wide range of angiogenic factors, including growth factors, chemokines, angiogenic enzymes, endothelial specific receptors, and adhesion molecules. </li></ul><ul><li>The angiogenic process is divided broadly into three major steps including the initiation of the angiogenic response, endothelial cell (EC) migration, proliferation and tube formation, and finally the maturation of the neovasculature. </li></ul>
  7. 8. “ Activated” endothelial cells  Proteases Degradation of BM EC migration EC proliferation Lumen formation Recruitment Of pericytes --new BM Fusion – New vessels Initiation of Blood Flow
  8. 9. <ul><li>Initiation of the angiogenic response </li></ul><ul><li>Angiogenesis is initiated in response to hypoxia, by the release of hypoxia inducible factors (HIF), which facilitate the release of angiogenic stimulators, which in turn lead to EC activation. </li></ul><ul><li>Activated EC secrete proteases, which degrade the extracellular tissue to facilitate endothelial penetration. </li></ul><ul><li>Proteases may be broadly divided into matrix metalloproteases (MMPs) and the plasminogen activator (PA) / plasmin system. </li></ul><ul><li>Both PAs and MMPs are secreted together with their inhibitors ensuring a stringent control of local proteolytic activity. </li></ul>
  9. 10. <ul><li>Endothelial cell migration, proliferation, and tube formation </li></ul><ul><li>Extracellular matrix degradation results in an increased concentration of various growth factors, which stimulate EC migration and proliferation. </li></ul><ul><li>After the initial period of migration, rapid EC proliferation begins, thus increasing the rate of sprout elongation. </li></ul><ul><li>These processes are also mediated by cell adhesion molecules. </li></ul>
  10. 11. <ul><li>Maturation of the neovasculature </li></ul><ul><li>The final phase of the angiogenic process involves maturation of the neovasculature. </li></ul><ul><li>After the formation of the capillary sprout, degradation of the newly formed ECM occurs again at the tip of the sprout, to allow further invasion. Interaction between the EC and ECM and the mesenchymal cells is a prerequisite for the formation of a stable vasculature. </li></ul><ul><li>The platelet-derived growth factor (PDGF) regulates the recruitment of pericytes and smooth muscle cells required for further stabilization of the new capillaries. </li></ul>
  11. 13. <ul><li>Regulation of Angiogenesis: </li></ul><ul><li>The healthy body controls angiogenesis through a series of &quot;on&quot; and &quot;off&quot; switches: </li></ul><ul><li>The main &quot;on&quot; switches are known as angiogenesis-stimulating growth factors </li></ul><ul><li>The main &quot;off switches&quot; are known as angiogenesis inhibitors </li></ul><ul><li>The normal, healthy body maintains a perfect balance of angiogenesis modulators. </li></ul>
  12. 14. <ul><li>When angiogenic growth factors are produced in excess over the angiogenesis inhibitors, the balance is tipped in favor of blood vessel growth. </li></ul><ul><li>When inhibitors are present in excess of stimulators, angiogenesis is stopped. </li></ul>
  13. 15. <ul><ul><li>Angiopoietin-1 </li></ul></ul><ul><ul><li>Del-1 </li></ul></ul><ul><ul><li>Fibroblast growth factors </li></ul></ul><ul><ul><li>acidic (aFGF) </li></ul></ul><ul><ul><li>basic (bFGF) </li></ul></ul><ul><ul><li>Follistatin </li></ul></ul><ul><ul><li>Granulocyte colony-stimulating factor (G-CSF) </li></ul></ul><ul><ul><li>Hepatocyte growth factor (HGF) /scatter factor (SF) </li></ul></ul><ul><ul><li>Interleukin-8 (IL-8) </li></ul></ul><ul><li>Vascular endothelial growth factor (VEGF) </li></ul><ul><li>Vascular permeability factor (VPF) </li></ul><ul><ul><li>Leptin </li></ul></ul><ul><ul><li>Midkine Angiogenin </li></ul></ul><ul><ul><li>Placental growth factor </li></ul></ul><ul><ul><li>Platelet-derived endothelial cell growth factor (PD-ECGF) </li></ul></ul><ul><ul><li>Platelet-derived growth factor-BB (PDGF-BB) </li></ul></ul><ul><ul><li>Pleiotrophin (PTN) </li></ul></ul><ul><ul><li>Progranulin </li></ul></ul><ul><ul><li>Proliferin </li></ul></ul><ul><ul><li>Transforming growth factor- α (TGF- α ) </li></ul></ul><ul><ul><li>Transforming growth factor- β (TGF- β ) </li></ul></ul><ul><ul><li>Tumor necrosis factor- α </li></ul></ul><ul><ul><li>(TNF- α ) </li></ul></ul><ul><li>Modulators of Angiogenesis: </li></ul><ul><li>Angiogenic growth factors </li></ul>
  14. 16. <ul><li>Some important growth factors </li></ul><ul><li>FGF : </li></ul><ul><li>The fibroblast growth factor (FGF) family with its prototype members FGF-1 (acidic FGF) and FGF-2 (basic FGF) consists to date of at least 22 known members. </li></ul><ul><li>FGFs stimulate a variety of cellular functions by binding to cell surface FGF-receptors in the presence of heparin proteoglycans. The FGF-receptor family is comprised of seven members and all the receptor proteins are single chain receptor tyrosine kinases that become activated through auto phosphorylation induced by a mechanism of FGF mediated receptor dimerization. </li></ul>
  15. 17. <ul><li>FGF-2 is a more potent angiogenic factor than VEGF or PDGF (platelet-derived growth factor), however, less potent than FGF-1. </li></ul><ul><li>FGF-1 (aFGF) and FGF-2 (bFGF) are important players in wound healing. They stimulate the proliferation of fibroblasts and endothelial cells that give rise to angiogenesis and developing granulation tissue, both increase blood supply and fill up a wound space/cavity early in the wound healing process. </li></ul>
  16. 18. <ul><li>VEGF : </li></ul><ul><li>Upregulation of VEGF is a major component of the physiological response to exercise and its role in angiogenesis is suspected to be a possible treatment in vascular injuries. </li></ul><ul><li>In vitro studies clearly demonstrate that VEGF is a potent stimulator of angiogenesis because in the presence of this growth factor plated endothelial cells will proliferate and migrate, eventually forming tube structures resembling capillaries. </li></ul>
  17. 19. <ul><li>VEGF causes a massive signaling cascade in endothelial cells. </li></ul><ul><li>Binding to VEGF receptor-2 (VEGFR-2) starts a tyrosine kinase signaling cascade that stimulates the production of factors that variously stimulate vessel permeability (eNOS, producting NO), proliferation/survival (bFGF), migration (ICAMs/VCAMs/MMPs) and finally differentiation into mature blood vessels as shown in figure. </li></ul>
  18. 21. <ul><li>Angiopoietins : </li></ul><ul><li>The angiopoietins, Ang1 and Ang2, are required for the formation of mature blood vessels, as demonstrated by mouse knock out studies. </li></ul><ul><li>Ang1 and Ang2 are protein growth factors which act by binding their receptors, Tie-1 and Tie-2; these receptors are tyrosine kinases. There is some controversy; it seems that cell signals are transmitted mostly by Tie-2; though some papers show physiologic signaling via Tie-1 as well. Thus, they can initiate cell signaling when ligand binding causes a dimerization that initiates phosphorylation on key tyrosines. </li></ul>
  19. 22. <ul><ul><li>Angioarrestin </li></ul></ul><ul><ul><li>Angiostatin </li></ul></ul><ul><ul><li>(plasminogen fragment) </li></ul></ul><ul><ul><li>Antiangiogenic antithrombin III </li></ul></ul><ul><ul><li>Cartilage-derived inhibitor (CDI) </li></ul></ul><ul><ul><li>CD59 complement fragment </li></ul></ul><ul><ul><li>Endostatin </li></ul></ul><ul><ul><li>(collagen XVIII fragment) </li></ul></ul><ul><ul><li>Fibronectin fragment </li></ul></ul><ul><ul><li>Heparinases </li></ul></ul><ul><ul><li>Heparin hexasaccharide fragment </li></ul></ul><ul><ul><li>Human chorionic gonadotropin (hCG) </li></ul></ul><ul><ul><li>Interferon α/β/γ </li></ul></ul><ul><ul><li>Interferon inducible protein (IP-10) </li></ul></ul><ul><ul><li>Interleukin-12 </li></ul></ul><ul><ul><li>Metalloproteinase inhibitors (MMPI) </li></ul></ul><ul><ul><li>2-Methoxyestradiol </li></ul></ul><ul><ul><li>Placental ribonuclease inhibitor </li></ul></ul><ul><ul><li>Plasminogen activator inhibitor </li></ul></ul><ul><ul><li>Platelet factor-4 (PF4) </li></ul></ul><ul><ul><li>Proliferin-related protein (PRP) </li></ul></ul><ul><ul><li>Retinoids </li></ul></ul><ul><ul><li>Tetrahydrocortisol-S </li></ul></ul><ul><ul><li>Thrombospondin-1 (TSP-1) </li></ul></ul><ul><ul><li>Vasculostatin Vasostatin (calreticulin fragment) </li></ul></ul><ul><li>Angiogenesis Inhibitors </li></ul>
  20. 23. <ul><li>Some important inhibitors </li></ul><ul><li>Angiostatin : </li></ul><ul><li>Angiostatin is a polypeptide of approximately 200 amino acids. </li></ul><ul><li>It is produced by the cleavage of plasminogen, a plasma protein that is important for dissolving blood clots. </li></ul><ul><li>Angiostatin binds to subunits of ATP synthase exposed at the surface of the cell embedded in the plasma membrane. (Before this recent discovery, ATP synthase was known only as a mitochondrial protein). </li></ul>
  21. 24. <ul><li>Endostatin : </li></ul><ul><li>Endostatin is a polypeptide of 184 amino acids. It is the globular domain found at the C-terminal of Type XVIII (18) collagen (a collagen found in blood vessels) cut off from the parent molecule. </li></ul>
  22. 26. <ul><li>Pathological angiogenesis </li></ul><ul><li>Angiogenesis dependent diseases result when new blood vessels either grow excessively or insufficiently. </li></ul><ul><li>Both angiogenesis insufficiency as well as excess can lead to various disorders. </li></ul>
  23. 27. <ul><li>Therapeutic angiogenesis </li></ul><ul><li>List of various conditions, which are likely to be benefited by the clinical manipulation of angiogenesis. </li></ul>Inhibition of angiogenesis Stimulation of angiogenesis Approved indications Approved indications Advanced cancer Chronic wound-diabetic ulcer Ocular neovascularization   Kaposi Sarcoma   Experimental indications Experimental indications Hemangiomas Myocardial ischemia Psoriasis Peripheral ischemia Rheumatoid arthritis Cerebral ischemia Endometriosis Reconstructive surgery Atherosclerosis Gastroduodenal ulcers
  24. 28. <ul><li>Angiogenesis can be induced mainly by two methods. </li></ul><ul><li>Either angiogenic proteins or endothelial progenitor cells synthesizing angiogenic growth factors can be injected directly into a site to stimulate blood vessel growth or </li></ul><ul><li>The right genes can be activated to induce a signaling cascade that would lead to angiogenesis. </li></ul><ul><li>The delivery of VEGF or bFGF to the ischemic tissue is the most tried intervention. </li></ul>
  25. 29. <ul><li>Applications </li></ul><ul><li>Peripheral vascular disease </li></ul><ul><li>Chronic wounds </li></ul><ul><li>Stroke </li></ul><ul><li>Cardiac disease </li></ul>
  26. 30. <ul><li>Challenges </li></ul><ul><li>VEGF forms leaky and tortuous vessels is known but the reason/mechanism is still unknown. </li></ul><ul><li>Whether a single or a combination of angiogenic molecules will be required to stimulate 'functional and sustainable' angiogenesis. For example, genetic studies have shown that the VEGF120 isoform alone is able to initiate, but not complete, the angiogenic program </li></ul>
  27. 31. <ul><li>Antiangiogenic therapy </li></ul><ul><li>Antiangiogenesis therapy is one of two types of drugs in a new class of medicines that restores health by controlling blood vessel growth. The other medication is called pro-angiogenic therapy. </li></ul><ul><li>Antiangiogenic therapy inhibits the growth of new blood vessels. </li></ul><ul><li>In many disease conditions, including disorders that cause blindness, arthritis, and cancer, angiogenesis inhibition is a &quot;common denominator&quot; approach to treating these diseases. </li></ul>
  28. 32. <ul><li>Antiangiogenic drugs exert their beneficial effects in a number of ways: </li></ul><ul><li>By disabling the agents that activate and promote cell growth, or </li></ul><ul><li>By directly blocking the growing blood vessel cells. </li></ul><ul><li>Antiangiogenic properties have been discovered in more than 300 substances, ranging from molecules produced naturally in animals and plants, such as green tea extract, to new chemicals synthesized in the laboratory, such as celecoxibe. </li></ul>
  29. 33. <ul><li>Strategies used in antiangiogenic therapy </li></ul><ul><li>In general, five strategies are being used as antiangiogenic therapies by the investigators: </li></ul><ul><li>i) Inhibitors of activated EC </li></ul><ul><li>ii) Inhibitors of EC intracellular signaling </li></ul><ul><li>iii) Inhibitors of ECM remodeling </li></ul><ul><li>iv) Inhibitors of adhesion molecules </li></ul><ul><li>v) Inhibitors of angiogenic mediators or their receptors </li></ul>
  30. 34. <ul><li>Applications </li></ul><ul><li>Ocular diseases </li></ul><ul><li>Rheumatoid arthritis </li></ul><ul><li>Cancer </li></ul>
  31. 35. <ul><li>Challenges </li></ul><ul><li>The long-term side effects of many antiangiogenic therapies are not known. </li></ul><ul><li>Many tumors do not 'shrink' during various antiangiogenic therapies. Thus, new imaging methods are needed to monitor vascular function and a therapeutic response in patients. </li></ul><ul><li>The angiogenic response may depend on the individual genetic constitution; hence, the administration of agents should be based on the biology of the individual, to generate maximum therapeutic benefit. </li></ul><ul><li>Since antiangiogenesis drugs could affect a developing fetus, they will probably not be used for pregnant women </li></ul>
  32. 36. <ul><li>Summary </li></ul><ul><li>Angiogenesis is a physiological process involving the growth of new blood vessels from pre-existing vessels. </li></ul><ul><li>The vascular network formation consists of multiple coordinated, sequential, and interdependent steps mediated by a wide range of angiogenic factors, including growth factors, chemokines, angiogenic enzymes, endothelial specific receptors, and adhesion molecules. </li></ul>
  33. 37. <ul><li>The angiogenic process is divided broadly into three major steps including the initiation of the angiogenic response, endothelial cell (EC) migration, proliferation and tube formation, and finally the maturation of the neovasculature. </li></ul><ul><li>The healthy body controls angiogenesis through a series of &quot;on&quot; and &quot;off&quot; switches: </li></ul><ul><li>The main &quot;on&quot; switches are known as angiogenesis-stimulating growth factors </li></ul><ul><li>The main &quot;off switches&quot; are known as angiogenesis inhibitors </li></ul>
  34. 38. <ul><li>In many serious disease states, the body loses control over angiogenesis. Angiogenesis dependent diseases result when new blood vessels either grow excessively or insufficiently. </li></ul><ul><li>Insufficient angiogenesis is characteristic of many disorders, including ischemic tissue injury or cardiac failure, where angiogenesis should be enhanced to improve the disease condition, which is known as Therapeutic angiogenesis. </li></ul><ul><li>Excessive vascular growth contributes to numerous disorders, and the list is growing rapidly. Cancer, arthritis, psoriasis, and blinding retinopathy are already known disorders associated with excess angiogenesis, where angiogenesis should be suppressed to improve the disease condition, which is known as Antiangiogenesis therapy. </li></ul>

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