Normal_Vascular_Growth_FINAL-2023 (1).pptx

CV-1: Normal vascular growth October 20th 2023 Pedro Del Corral, Ph.D. M.D. Associate Professor Department of Physiology & Pathology Burrell College of Osteopathic Medicine 1 Reading assingments • Robbins & Cotran Pathology 10th edition: • Angiogenesis & Tissue repair: 103-107 Chapter 3 • Angiog...

CV-1: Normal vascular growth October 20th 2023 Pedro Del Corral, Ph.D. M.D. Associate Professor Department of Physiology & Pathology Burrell College of Osteopathic Medicine 1 Reading assingments • Robbins & Cotran Pathology 10th edition: • Angiogenesis & Tissue repair: 103-107 Chapter 3 • Angiogenesis & Neoplasia 305-306 Chapter 7 • Guyton & Hall Medical Physiology 13th Edition, p. 209-210 (Chapter 17) 2 Objectives • Draw the molecular & cellular mechanisms involved in production of VEGF. • Describe the steps in new vessel growth. • Identify the initial “Switch” for neovascularization. • Describe the clinical relevance of angiogenesis 3 • If the metabolism in a tissue is increased for a prolonged period, vascularity increases, a process generally called angiogenesis ; if the metabolism is decreased, vascularity decreases. • Thus, actual physical reconstruction of the tissue vasculature occurs to meet the needs of the tissues. This reconstruction occurs rapidly (within days). • also occurs rapidly in new growth tissue, such as in cancerous tissue, but occurs much more slowly in old, well-established tissues. • Time required for long-term regulation: a few days in the neonate or as long as months in older adults. The final degree of response is much better in younger than in older tissues. 4 Role of Oxygen in Long-Term Regulation. • One example of this is increased vascularity in tissues of animals that live at high altitudes, where the atmospheric oxygen is low. • In premature babies who are put into oxygen tents for therapeutic purposes, the excess oxygen causes almost immediate cessation of new vascular growth in the retina of the premature baby’s eyes and even causes degeneration of some of the small vessels that already have formed. • When the infant is taken out of the oxygen tent, explosive overgrowth of new vessels then occurs to make up for the sudden decrease in available oxygen. Often, so much overgrowth occurs that the retinal vessels grow out from the retina into the eye’s vitreous humor, eventually causing blindness, a condition called retrolental fibroplasia . 5 Importance of Vascular Growth Factors in Formation of New Blood Vessels. • Four factors that have been well characterized are vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and angiogenin, each of which has been isolated from tissues that have inadequate blood supply. • A ↓ in tissue oxygen  ↑expression of hypoxia inducible factors (HIFs)  upregulate gene expression and the formation of vascular growth factors (also called angiogenic factors ). • Angiogenesis begins with new vessels sprouting from other small vessels. 6 Angiogenesis begins with new vessels sprouting from other small vessels. • 1st dissolution of the basement membrane of the endothelial cells at the point of sprouting. • 2nd rapid reproduction of new endothelial cells, which stream outward through the vessel wall in extended cords directed toward the source of the angiogenic factor. The cells in each cord continue to divide and rapidly fold over into a tube. • 3rd the tube connects with another tube budding from another donor vessel (another arteriole or venule) and forms a capillary loop through which blood begins to flow. • 4th If the flow is great enough, smooth muscle cells eventually invade the wall, so some of the new vessels eventually grow to be new arterioles or venules or perhaps even larger vessels. Thus, angiogenesis explains how metabolic factors in local tissues can cause growth of new vessels. 7 Angiogenesis – Tissue Repair • Repair - refers to the restoration of tissue architecture and function after an injury. • Goal is to restore normal function with native parenchymal and connective tissue • For instance, inflammatory response to microbes and injured tissues not only serves to eliminate these dangers but also sets into motion the process of repair. • Repair of damaged tissues occurs by two processes: regeneration, which restores normal cells, and scarring, the deposition of connective tissue. 8 Angiogenesis – Tissue Repair • Regeneration. Some tissues are able to replace the damaged components and essentially return to a normal state. • Regeneration may occur by proliferation of differentiated cells that survive the injury and retain the capacity to proliferate, tissue stem cells and their progenitors contribute to the restoration of damaged tissues. • Figure 3.24Mechanisms of tissue repair: regeneration and scar formation. Following mild injury, which damages the epithelium but not the underlying tissue, resolution occurs by regeneration, but after more severe injury with damage to the connective tissue, repair is by scar formation. 9 Angiogenesis – Cell and Tissue Regeneration • Several cell types proliferate during tissue repair. These include the remnants of the injured tissue (which attempt to restore normal structure), vascular endothelial cells (to create new vessels that provide the nutrients needed for the repair process), and fibroblasts (the source of the fibrous tissue that forms the scar to fill defects that cannot be corrected by regeneration). • Angiogenesis is the process of new blood vessel development from existing vessels. It is critical in: • 1. healing at sites of injury, in the development of collateral circulations at sites of ischemia • 2. allowing tumors to increase in size beyond the constraints of their original blood supply. • 3. relevance to therapy - therapies to either: • augment the process • inhibit it 10 Angiogenesis – involves sprouting of new vessels from existing ones and consists of the following steps • 1. Vasodilation in response to nitric oxide and increased permeability induced by vascular endothelial growth factor (VEGF). • 2. Separation of pericytes from the abluminal surface and breakdown of the basement membrane to allow formation of a vessel sprout. • 3. Migration of endothelial cells toward the area of tissue injury. • 4. Proliferation of endothelial cells just behind the leading front (“tip”) of migrating cells. • 5. Remodeling into capillary tubes. • 6. Recruitment of periendothelial cells (pericytes for small capillaries and smooth muscle cells for larger vessels) to form the mature vessel. • 7. Suppression of endothelial proliferation and migration and deposition of the basement membrane. 11 • Figure 3.28Angiogenesis. In tissue repair, angiogenesis occurs mainly by sprouting of new vessels. The steps in the process and the major signals involved are illustrated. The newly formed vessel joins up with other vessels (not shown) to form the new vascular bed. ECM, Extracellular matrix; MMPs, matrix metalloproteinases; VEGF, vascular endothelial growth factor. 12 Mechanisms of Angiogenesis • The process of angiogenesis involves several signaling pathways, cell–cell interactions, ECM proteins, and tissue enzymes. • VEGFs, mainly VEGF-A, stimulate both migration and proliferation of endothelial cells, thus initiating the process of capillary sprouting in angiogenesis. • VEGF promotes vasodilation by stimulating the production of NO and contributes to the formation of the vascular lumen. • Fibroblast growth factors (FGFs), stimulate the proliferation of endothelial cells. They also promote the migration of macrophages and fibroblasts to the damaged area. • Angiopoietins 1 and 2 (Ang 1 and Ang 2) are growth factors that play a role in angiogenesis and the structural maturation of new vessels. 13 Mechanisms of Angiogenesis • The maturation of blood vessels is then stabilized by smooth muscle, pericytes, and connective tissue • PDGF recruits smooth muscle cells • TGF-β suppresses endothelial proliferation and migration and enhances the production of ECM proteins. Angiogenesis in Cancer 14 Angiogenesis in Cancer • Even if a solid tumor possesses all the genetic aberrations that are required for malignant transformation, it cannot enlarge beyond 1 to 2 mm in diameter unless it has the capacity to induce angiogenesis. • Key for oxygen, nutrients, and waste can diffuse from existing blood vessels. • Neovascularization also stimulate the growth of adjacent tumor cells by secreting growth factors such as insulin-like growth factors (IGFs) and PDGF. • These vessels are not entirely normal: • Are leaky and dilated and have a haphazard pattern of connection. How do growing tumors develop a blood supply 15 Angiogenesis in Cancer • How do growing tumors develop a blood supply? The current paradigm is that angiogenesis is controlled by a balance between angiogenesis promoters and inhibitors; in angiogenic tumors this balance is skewed in favor of promoters. • 1. Early in their development, most human tumors do not induce angiogenesis. • 2. Starved of nutrients, these tumors remain small or in situ, possibly for years, until an angiogenic switch terminates this stage of quiescence. • The molecular basis of the angiogenic switch involves increased local production of angiogenic factors and/or loss of angiogenic inhibitors. The sources of these factors include: • tumor cells • infiltrating inflammatory cells (e.g., macrophages) or • other tumor-associated stromal cells, and the ECM. What enhances the production of pro-angiogenic factors 16 Angiogenesis in Cancer: Alterations that enhance the production of proangiogenic factors • 1. Relative lack of oxygen due to hypoxia stabilizes HIF1α, an oxygensensitive transcription factor that activates the transcription of the proangiogenic cytokines: • VEGF and basic fibroblast growth factor (bFGF). • create an angiogenic gradient that stimulates the proliferation of endothelial cells and guides the growth of new vessels toward the tumor. • 2. Driver mutations in certain tumor suppressors and oncogenes favor angiogenesis. • p53 stimulates the expression of anti-angiogenic molecules such as thrombospondin-1 and represses the expression of pro-angiogenic molecules such as VEGF. Thus, loss of p53 provides a more permissive environment for angiogenesis. • 3. Proteases 17 Angiogenesis in Cancer • The idea that angiogenesis is essential for solid tumors to grow to clinically significant sizes provided a powerful impetus for the development of therapeutic agents that block angiogenesis. • Bevacizumab, a monoclonal antibody that neutralizes VEGF activity and is approved for treatment of multiple cancers. However, angiogenesis inhibitors have not been nearly as effective as was hoped; they can prolong life • but usually for only a few months and at very high financial cost. 18 Angiogene sis (Short List) •Controlled Neovascularization • Normal formation of new blood vessels: • Embryogenesis • Growth • Exercise • Female repro tract/month • Wound healing •Uncontrolled Neovascularization •Aberrant formation of new blood vessels: • • • • Retinopathy Infarctions Infections Neoplasia (tumor formation) • Renal Cell Carcinoma (VHL) 19 Hif -1α • Oxygen levels high cells contain small amounts of HIF • Oxygen level low HIF binds to EPO and other genes • VHL can physically interact with HIF required for degradation at normal oxygen levels. 20 HIF--------------------Endostatin inhibits angiogenesis • Hypoxia- causes HIF 1α – migrate from the cytoplasm to the nucleus • • Hif1A = Angiogenesis VEGF = Angiogenesis • Normal angiogenesis depends on the intricate balance between angiogenic (VEGF, FGF, TGF-B) & angiostatic factors, such as such as angiostatin, endostatin, and the thrombospondin. • Endostatin, a cleavage product of the COOH-terminal of collagen, is a potent inhibitor of EC proliferation and migration and angiogenesis mediated by interaction with integrins on ECs 21 Hypoxia signalling in cancer and approaches to enforce tumour regression, Jacques Pouysségur, Frédéric Dayan & Nathalie M. Mazure. Nature 441, 437-443(25 May 2006) • Angiogenesis- Disease & Angiogenesis Therapy: Angiogenesi s & Disease Obesity & Lipogenesis Atherosclerosis Retinopathy Neoplasia Von Hippel-Lindau disease (tumors in multiple organs, brain, spinal cord, eyes, kidneys) 22 Myocardial Infarction • Anastomotic channels, known as collateral vessels, connect coronary artery with that supplied by another. • Clinical significance of coronary collaterals • The clinical relevance has been disputed repeatedly since the anastomoses are often incapable of restoring flow to normal levels. In fact, the presence of collaterals was sometimes even assumed to signify a worsening prognosis. 23 Angiogenic Disease & Repair Myocardial infarction Do new vessels form in the heart after a MI? Granulation Scar A) `24 hrs., Post MI- Coagulative necrosis; B) 3-4 days neutrophils infiltrate; C) 7-10 days removal of necrosis by phagocytosis; D) Granulation (!); E) Necrosis replaced by dense 24 • B: capillary density as identified by immunostaining of endothelial cells (green), sarcolemma (red), and nuclei (blue). Note that capillaries appear yellow because of overlap with red sarcolemmal staining; n 8 and n 6 subjects for untrained and trained groups, respectively 25