On vascular endothelial growth factor B and platelet-derived growth factor C : two members of the VEGF/PDGF family of growth factors

Sammanfattning: Vascular endothelial growth factors (VEGFs), platelet-derived growth factors (PDGFs) and their receptors are important for normal development. They have also been implicated in many pathological conditions. VEGFs have been shown to play an important role in the development of both blood and lymphatic vessels. PDGFs on the other hand, are important regulators of the connective tissue cells of both the vascular network and other organs systems. The focus of the work presented in this thesis has been to elucidate the role of two members of the VEGF/PDGF family of growth factors, namely VEGF-B and PDGF-C. Embryonic analysis at the mRNA and protein level showed that VEGF-B was expressed in several organs, with highest expression in the developing muscles. VEGF-B was not detected in endothelial cells, where its receptor VEGFR-1 is expressed, which suggested that VEGF-B acts in a paracrine way. The expression of the two isoforms, VEGF-B167 and VEGF-B186 were investigated using techniques that can distinguish the two isoforms. The results showed that the VEGF-B167 isoform is predominantly expressed in most tissues. The VEGF-B186 isoform is expressed at lower levels and only in a limited numbers of organs. Moreover, the VEGF-B186 isoform is upregulated in mouse and human tumour cell lines and primary tumours compared with their corresponding normal tissues. These data suggest a fine genetic control of the expression of the two isoforms of VEGF-B, implying tissue- and cell-specific roles for the two VEGF-B isoforms. To elucidate the function in vivo, a VEGF-B knockout mouse strain was generated. The results showed that VEGF-B is not required for normal development of the cardiovascular system or for angiogenesis in adults. However, adult VEGF-B deficient mice have an atrial conduction abnormality characterised by a prolonged PQ interval in the electrocardiogram; thus VEGF-B appears to be required for normal heart function in adult animals. The second growth factor, PDGF-C contains a domain structure not present in other members of the VEGF/PDGF family. Following the signal sequence, PDGF-C contains an N-terminal CUB-domain and, in the C-terminus, the VEGF/PDGF homology domain. PDGF-C is synthesised as an inactive precursor protein that has to be proteolytically processed in the N-terminus before it can bind and activate its receptor, PDGFR-a. Expression analysis during mouse development suggests that PDGF-C acts in both paracrine and autocrine ways.