VEGF Receptor Signal Transduction

The family of vascular endothelial growth factors (VEGFs) currently includes VEGF-A, -B, -C, -D, -E, and placenta growth factor (PlGF). Several of these factors, notably VEGF-A, exist as different isoforms, which appear to have unique biological functions. The VEGF family proteins bind in a distinct pattern to three structurally related receptor tyrosine kinases, denoted VEGF receptor-1, -2, and -3. Neuropilins, heparan-sulfated proteoglycans, cadherins, and integrin αvβ3 serve as coreceptors for certain but not all VEGF proteins. Moreover, the angiogenic response to VEGF varies between different organs and is dependent on the genetic background of the animal. Inactivation of the genes for VEGF-A and VEGF receptor-2 leads to embryonal death due to the lack of endothelial cells. Inactivation of the gene encoding VEGF receptor-1 leads to an increased number of endothelial cells, which obstruct the vessel lumen. Inactivation of VEGF receptor-3 leads to abnormally organized vessels and cardiac failure. Although VEGF receptor-3 normally is expressed only on lymphatic endothelial cells, it is up-regulated on vascular as well as nonvascular tumors and appears to be involved in the regulation of angiogenesis. A large body of data, such as those on gene inactivation, indicate that VEGF receptor-1 exerts a negative regulatory effect on VEGF receptor-2, at least during embryogenesis. Recent data imply a positive regulatory role for VEGF receptor-1 in pathological angiogenesis. The VEGF proteins are in general poor mitogens, but binding of VEGF-A to VEGF receptor-2 leads to survival, migration, and differentiation of endothelial cells and mediation of vascular permeability. This review outlines the current knowledge about the signal transduction properties of VEGF receptors, with focus on VEGF receptor-2. Vascular endothelial growth factors (VEGFs) constitute an expanding family of growth factors that have received considerable attention from the basic research community but also from clinically active scientists and pharmaceutical companies. The reason for the interest in this growth factor family is its pivotal role in formation of the vascular tree during embryogenesis, as well as in formation of new vessels from preexisting ones, a process called angiogenesis. Normally, angiogenesis is tightly regulated, but in diseases such as cancer, diabetes, and chronic inflammatory diseases, excess VEGF is produced, leading to hyperstimulated and dysfunctional vessels. VEGF proteins bind to cell surface-expressed receptor molecules, denoted VEGF receptor-1, -2, and -3. VEGF receptor-1 and -2 are expressed on endothelial cells in blood vessels, whereas VEGF receptor-3 is expressed on cells in lymphatic vessels. Inactivation of certain of the genes encoding the VEGF proteins or the VEGF receptors is incompatible with normal vascular development. This review outlines the current knowledge about the role of the VEGF proteins and VEGF receptors in the formation of new blood vessels.

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