VEGF-A, VEGF-D and VEGF-DΔNΔC induced intimal hyperplasia in carotid arteries

Background The role of vascular endothelial growth factors (VEGFs) in intimal hyperplasia and atherogenesis remains unknown. Several studies have suggested that some members of the VEGF family reduce intimal hyperplasia, but others have proposed that VEGFs accelerate restenosis and atherosclerosis. This investigation conducted a comparative study with adenoviruses encoding different VEGFs in a rabbit carotid artery collar model of intimal hyperplasia in order to analyze the role of VEGFs in the formation of intimal hyperplasia. Materials and methods Intimal hyperplasia was induced in the carotid arteries of cholesterol fed New Zealand White rabbits using a silastic collar. Adenoviral vectors encoding VEGF-A, VEGF-B, VEGF-C, VEGF-C-Delta N Delta C, VEGF-D and VEGF-D-Delta N Delta C were delivered to the adventitia using the collar as a gene delivery device. Adeno-LacZ was used as a control. Results A significant (P < 0.01) increase in the intima/media ratio was observed in the arteries transduced with VEGF-A, VEGF-D and VEGF-D-Delta N Delta C. There was a significant increase in the number of proliferating cells in the adventitia, media and intima of the VEGF-A, VEGF-D and the VEGF-D-Delta N Delta C transduced arteries. The majority of medial smooth muscle cells in these arteries had a synthetic phenotype. The presence of matrix metalloproteinase-2 (MMP-2) and MMP-9 in the VEGF-A, VEGF-D and the VEGF-D-Delta N Delta C transduced arteries was significantly increased. A significant positive correlation was observed between adventitial angiogenesis and intimal hyperplasia. Conclusions Adventitial delivery of adenoviruses encoding VEGF-A, VEGF-D and VEGF-D-Delta N Delta C increased intimal hyperplasia in the rabbit collar model. Adventitial angiogenesis correlated positively with the intimal hyperplasia. These results indicated that efficient adventitial production of VEGF-A, VEGF-D and VEGF-D-Delta N Delta C can cause thickening of the inner layer of the artery in rabbits.