Angiogenesis o Blood vessels formation in adults is known as angiogenesis or neovascularization. It can occur by two ways:- 1. Angiogenesis from pre-existing blood vessels The major steps in this process are i. Vasodilatation by NO, and VEGF-induced increased permeability of the pre-existing vessel. ii. Proteolytic degradation of the basement membrane by metalloproteinases (MMPs) and disruption of cell-to-cell contact between endothelial cells by plasminogen activator. iii. Migration of endothelial cells towards angiogenic stimulus. iv. Proliferation of endothelial cells, just behind the leading front of migrating cells. v. Maturation of endothelial cells. vi. Recruitment of periendothelial cells (pericytes and vascular smooth muscle cells) to form the mature cells. 2. Angiogenesis from endothelial precursor cells (EPCs) EPCs can be recruited from the bone marrow into tissues to initiate angiogenesis. Growth factors involved in the process of angiogenesis o VEGF is the most important growth factor in adult tissues undergoing angiogenesis. o The most important receptor for VEGF is VEGFR-2, a tyrosine kinase receptor. o VEGF induces the migration of EPCs in the bone marrow, and enhances the proliferation and differentiation of these cells at sites of angiogenesis. o FGF 2 can also stimulate endothelial cell proliferation, differentiation and migration. o Newly formed vessels are fragile and need to become stabilized, which requires the recruitment of pericytes and smooth muscle cells (peri-endothelial cells). Angiopoietin 1 and 2 (Ang 1 & 2), PDGF and TGF-fl participate in stabilization process. Remember o VEGF transcription is regulated by the transcription factor HIF, which is induced by hypoxia.