Molecular Diversity of VEGF-A as a Regulator of Its Biological Activity

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Abstract
The vascular endothelial growth factor (VEGF) family of proteins regulates blood flow, growth, and function in both normal physiology and disease processes. VEGF‐A is alternatively spliced to form multiple isoforms, in two subfamilies, that have specific, novel functions. Alternative splicing of exons 5–7 of the VEGF gene generates forms with differing bioavailability and activities, whereas alternative splice‐site selection in exon 8 generates proangiogenic, termed VEGFxxx, or antiangiogenic proteins, termed VEGFxxxb. Despite its name, emerging roles for VEGF isoforms on cell types other than endothelium have now been identified. Although VEGF‐A has conventionally been considered to be a family of proangiogenic, propermeability vasodilators, the identification of effects on nonendothelial cells, and the discovery of the antiangiogenic subfamily of splice isoforms, has added further complexity to their regulation of microvascular function. The distally spliced antiangiogenic isoforms are expressed in normal human tissue, but downregulated in angiogenic diseases, such as cancer and proliferative retinopathy, and in developmental pathologies, such as Denys Drash syndrome and preeclampsia. Here, we examine the molecular diversity of VEGF‐A as a regulator of its biological activity and compare the role of the pro‐ and antiangiogenic VEGF‐A splice isoforms in both normal and pathophysiological processes.