Vascular Endothelial Growth Factors ( VEGFs )-Role in Perivascular Therapeutic Angiogenesis and Diabetic Macrovascular Disease

Angiogenesis is the process by which new blood vessels are formed from existing vessels. Vascular endothelial growth factors (VEGFs) VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F and placental growth factor (PlGF) are key molecules in the process of angiogenesis. The ability of VEGFs to induce angiogenesis can be used for therapeutic purposes but these molecules also play a critical role in many pathological conditions. Recent advancements in vascular research have enhanced our understanding of their functions. However, only limited information is available about therapeutic and pathological roles of VEGFs in vascular compartments. In this study we evaluated the roles of VEGFs in perivascular therapeutic angiogenesis and in pathogenesis of diabetic atherosclerosis. We used a localized perivascular gene transfer model to study therapeutic angiogenesis produced by VEGFs. Perivascular gene transfer has been used in preclinical and clinical trials for therapeutic angiogenesis, intimal hyperplasia and vein graft survival. Gene transfer was done using silastic collars placed around the carotid arteries of New Zealand White rabbits. VEGF-A, B, -C, -C∆N∆C, -D, -D∆N∆C, PlGF-2 and Lac-Z gene delivery were carried out using adenoviral vectors. Among the VEGF family members, VEGF-A, VEGF-D, VEGF-D∆N∆C and PlGF-2 were most efficient in inducing angiogenesis and VEGF-A, VEGF-D and VEGF-D∆N∆C also produced significant intimal hyperplasia. Increased inflammation was seen in VEGF-A, VEGF-B and PlGF-2 transduced arteries. Endogenous VEGF-A expression was increased in the PlGF-2 transduced arteries and PlGF-2 mediated angiogenesis was blocked by sVEGFR-1 and sVEGFR-2. In vitro studies have suggested that diabetes increases VEGF expression. Using an animal model of diabetes with hyperlipidemia, we studied the effects of diabetes on atherosclerosis, including VEGFs expression in atherosclerotic lesions and plaque angiogenesis. Diabetes was induced in Watanabe heritable hyperlipidemic (WHHL) rabbits by intravenous Alloxan injections. Accelerated atherosclerosis, inflammatory response and significant increases in RAGE, NFkB, VEGF-A, VEGF-D, VEGFR-1, and VEGFR-2 expression were seen in diabetic animals. An increased tendency towards plaque angiogenesis was also seen in diabetic animals. We conclude that VEGF-A, VEGF-D, -D∆N∆C and PlGF-2 gene transfer significantly increase angiogenesis in adventitia. Endogenous VEGF-A plays a key role in mediating angiogenic responses of PlGF-2. Perivascular therapeutic angiogenesis using VEGFs should be done with a caution. There is significantly increased intimal hyperplasia with VEGF-A, VEGF-D, -D∆N∆C and inflammation with VEGF-A, VEGF-B and PlGF-2 gene transfer. Diabetes produced accelerated atherosclerosis and increased VEGF-A, VEGF-D, VEGFR-1 and VEGFR-2 expression in atherosclerotic lesions. The presence of VEGFs in diabetic atherosclerotic plaques is presumably modulated by the macrophages, NFkB and RAGE. National Library of Medicine Classification: QZ 52, WK 810, WG 550, QU 107, WG 500 Medical Subject Headings: angiogenesis inducing agents; neovascularization, pathologic; gene therapy; connective tissue; atherosclerosis; Adenoviridae; vascular endothelial growth factors; carotid arteries; tunica intima/pathology; hyperplasia; diabetes mellitus, experimental; inflammation mediators; disease models, animal; rabbits