VEGF and its receptors are required for vasculogenesis (the de novo formation of blood vessels from differentiating endothelial cells, as occurs during embryonic development) and angiogenesis under normal (wound healing, corpus luteum formation) and pathologic processes (tumor angiogenesis, inflammatory conditions such as rheumatoid arthritis). VEGF-A is a heparin-binding glycoprotein with at least four isoforms (splice variants) that regulates blood vessel formation by binding to the RTKs VEGFR1 and VEGFR2, which are expressed on all ECs in addition to a subset of hematopoietic cells (Fig. 80-8). VEGFR2 regulates EC proliferation, migration, and survival, while VEGFR1 may act as an antagonist. | Chapter 080. Cancer Cell Biology and Angiogenesis Part 17 VEGF and its receptors are required for vasculogenesis the de novo formation of blood vessels from differentiating endothelial cells as occurs during embryonic development and angiogenesis under normal wound healing corpus luteum formation and pathologic processes tumor angiogenesis inflammatory conditions such as rheumatoid arthritis . VEGF-A is a heparin-binding glycoprotein with at least four isoforms splice variants that regulates blood vessel formation by binding to the RTKs VEGFR1 and VEGFR2 which are expressed on all ECs in addition to a subset of hematopoietic cells Fig. 80-8 . VEGFR2 regulates EC proliferation migration and survival while VEGFR1 may act as an antagonist of R1 in ECs but is probably also important for angioblast differentiation during embryogenesis. Tumor vessels appear to be more dependent on VEGFR signaling for growth and survival than normal ECs. While VEGF signaling is a critical initiator of angiogenesis this is a complex process regulated by additional signaling pathways Fig. 80-9 . The angiopoietin Angl produced by stromal cells binds to the EC RTK Tie-2 and promotes the interaction of ECs with the ECM and perivascular cells such as pericytes and smooth-muscle cells to form tight non-leaky vessels. PDGF and basic fibroblast growth factor bFGF help to recruit these perivascular cells. Angl is required for maintaining the quiescence and stability of mature blood vessels and prevents the vascular permeability normally induced by VEGF and inflammatory cytokines. For tumor cell-derived VEGF to initiate sprouting from host vessels the stability conferred by the Ang1 Tie2 pathway must be perturbed this occurs by the secretion of Ang2 by ECs that are undergoing active remodeling. Ang2 binds to Tie2 and is a competitive inhibitor of Angl action under the influence of Ang2 preexisting blood vessels become more responsive to remodeling signals with less adherence of ECs to stroma and .
