Platelet-derived growth factor. PDGF is a family of several closely related proteins, each consisting of two chains (designated by pairs of letters). Three isoforms of PDGF (AA, AB, and BB) are constitutively active, while PDGF-CC and PDGF-DD must be activated by proteolytic cleavage. PDGF is stored in platelet granules and is released on platelet activation. Although originally isolated from platelets (hence the name), it also is produced by many other cells, including activated macrophages, endothelium, smooth muscle cells, and a variety of tumors. All PDGF isoforms exert their effects by binding to two cell surface receptors (PDGFR α and β), both having intrinsic tyrosine kinase activity. PDGF induces fibroblast, endothelial, and smooth muscle cell proliferation and matrix synthesis, and is chemotactic for these cells (and inflammatory cells), thus promoting recruitment of the cells into areas of inflammation and tissue injury.
Vascular endothelial growth factor. Vascular endothelial growth factors (VEGFs)—VEGF-A, -B, -C, and -D, and PIGF (placental growth factor)—are a family of homodimeric proteins. VEGF-A is generally referred to simply as VEGF; it is the major factor responsible for angiogenesis, inducing blood vessel development, after injury and in tumors. In comparison, VEGF-B and PIGF are involved in embryonic vessel development, and VEGF-C and -D stimulate both angiogenesis and lymphatic development (lymphangiogenesis). VEGFs also are involved in the maintenance of endothelial cells lining mature vessels. Its expression is highest in epithelial cells adjacent to fenestrated endothelium (e.g., podocytes in the kidney, pigment epithelium in the retina, and choroid plexus in the brain). VEGF induces angiogenesis by promoting endothelial cell migration and proliferation (capillary sprouting), and the formation of the vascular lumina. VEGFs also induce vascular dilation and increase vascular permeability. As might be anticipated, hypoxia is the most important inducer of VEGF production through pathways that involve activation of the transcription factor hypoxia-inducible factor (HIF-1). Other VEGF inducers—produced at sites of inflammation or wound healing—include PDGF and TGF-α.
VEGFs bind to a family of receptor tyrosine kinases (VEGFR-1, -2, and -3). VEGFR-2 is highly expressed in endothelium and is the most important for angiogenesis. Antibodies against VEGF are approved for the treatment of several tumors such as renal and colon cancers because cancers require angiogenesis for their spread and growth. Anti-VEGF antibodies also are used in the treatment of a number of ophthalmic diseases, including: “wet” age-related macular degeneration (AMD a disorder of inappropriate angiogenesis and vascular permeability that causes adult-onset blindness); the retinopathy of prematurity; and the leaky vessels that lead to diabetic macular edema. Finally, increased levels of soluble versions of VEGFR-1 (s-FLT-1) in pregnant women may contribute to preeclampsia (hypertension and proteinuria) by “sopping up” the free VEGF required for maintaining normal endothelium.