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
VEGF(xxx), or antiangiogenic
proteins, termed
VEGF(xxx)b. 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.