Biological activities of novel Platelet-derived growth factors, PDGF-C and PDGF-D

Abstract: Platelet-derived growth factors (PDGFs) belong to the PDGF/VEGF (vascular endothelial growth factor) family of growth factors. Members of this family share a common structural feature, a conserved PDGF/VEGF homology domain, containing eight invariant cysteine residues. PDGFs form disulphidelinked dimers and exert their biological functions by binding to, and activating two receptor tyrosine kinases, PDGFR-alpha and PDGFR-beta. For almost two decades, PDGF-A and PDGF-B were the only PDGF isoforms known to exist, but recently PDGF-C and PDGF-D were also identified. PDGF-C and PDGF-D are expressed as latent growth factors with a two-domain structure consisting of an N-terminal CUB domain, and a C-terminal PDGF/VEGF homology domain. Both factors require proteolytical removal of the CUB domain, in order to become active. PDGF-AA, PDGF-BB, PDGF-AB and PDGF-CC isoforms are able to activate PDGFR-alpha homodimers, whereas PDGF-BB and PDGF-DD activate PDGFR-beta homodimers. PDGF-AB, PDGF-BB, PDGF-CC and PDGF-DD can also activate PDGFR-alphabeta heterodimers in cells co-expressing both receptor subtypes. PDGFs are known mitogens for mesenchymal cells, and are essential in embryonic development. It is also well established that PDGFs are involved in several pathological settings, including tumor development, wound healing, fibrotic reactions, and atherosclerosis. An attractive clinical application for PDGFs is therapeutic angiogenesis, based on their ability to stimulate angiogenesis and to recruit mural cells. VEGF treatment produces extensive amounts of new blood vessels, but in order to generate functional, persistent blood vessels, recruitment of SMCs and pericytes is important. In this work, the biological activities of PDGF-C and PDGF-D were explored, including the expression pattern of PDGF-D in developing and adult tissue, overexpression of PDGF-C or PDGF-D in transgenic mice, and gene delivery of PDGF-C or PDGF-D into mouse ear using recombinant adenovirus. During mouse development PDGF-D was detected in several tissues, including myocardium, skeletal muscle, epithelium, liver, kidney, cartilage and some blood vessels. The expression pattern is different compared to PDGF-B, which is mainly expressed in growing blood vessels, suggesting distinct functions of PDGF-B and PDGF-D in PDGFR-beta signaling. In adult mice, PDGF-D was also detected in several hormoneproducing cells. Heart-specific overexpression of full-length PDGF-C, or the active form of PDGF-D (the so-called core domain), induced cardiac fibrosis, hypertrophy and cardiac failure, as well as several vascular changes, including dilation of microvessels and increased density of SMC coated vessels. In addition, PDGF-D stimulated proliferation of vSMCs, leading to thickened arterial walls. The PDGF-C transgenic mice developed sex-dependent phenotypes. In male mice, a hypertrophic response was induced, whereas females developed dilated cardiomyopathy. Adenovirally encoded PDGF-C induced capillary sprouting and PDGF-D stimulated arterialization of vessels. We suggest that PDGF-C and PDGF-D are potent modulators of vascular growth, as well as powerful mitogens for connective tissue cells.