VEGF Gene Transfer Reduces Intimal Thickening via Increased Production of Nitric Oxide in Carotid Arteries

Abstract

Thickening of the arterial intima and smooth muscle cell (SMC) proliferation remain major problems after vascular surgery and other types of vascular manipulations. We studied the effect of endothelial cell (EC)-specific vascular endothelial growth factor (VEGF) gene transfer on the thickening of the intima using a silicone collar inserted around carotid arteries that acted both as the agent that caused intimal SMC growth and as a reservoir for the transfected gene. The model preserved EC integrity and permitted direct extravascular gene transfer without any intravascular manipulation. Compared to beta-galactosidase (lacZ)-transfected control arteries, plasmid/liposome-mediated VEGF gene transfer significantly reduced intimal thickening 1 week after the gene transfer. Administration to the experimental animals of the nitric oxide (NO) synthase inhibitor L-NAME abolished the difference in intimal thickening between VEGF and lacZ-transfected arteries. Furthermore, VEGF caused NO release from cultured human umbilical vein EC. It is concluded that extravascular VEGF gene transfer attenuates intimal growth and could be useful for the prevention of intimal thickening during vascular surgery. Our results further suggest that VEGF may reduce SMC proliferation via a mechanism that involves VEGF-induced NO production from the endothelium.

Efficient adventitial gene delivery to rabbit carotid artery with cationic polymer–plasmid complexes

“…13 Adventitial delivery of plasmids and oligonucleotides has also been reported in a number of other applications. 8,10,22 In human atherosclerotic arteries, 5% transfection efficiency via the intravascular route has been recently achieved with adenoviruses.…”

“…6,8,23 Furthermore, human lesions are frequently rich in connective tissue and contain only a limited number of transfectable cells in the intimal part of the lesion. To circumvent these problems adventitial gene delivery can be performed with a silastic or biodegradable collar, 13 biodegradable gel, 5 or direct injection into adventitia. 22 It is concluded that local gene transfer with cationic polymer-plasmid complexes provides an efficient way for the treatment of arterial diseases during vascular surgery, such as prosthesis and anastomosis operations and by-pass surgery.…”

“…[1][2][3][4][5][6][7][8][9][10][11] To date, viral systems have been more efficient than nonviral vehicles in vascular gene transfer. 10,12,13 However, the use of viral vectors in gene therapy has raised questions concerning their immunogenicity, oncogenic properties and unknown long-term effects. 14 Such safety concerns have not been linked to nonviral delivery of plasmid DNA.…”

“…Efficient arterial gene transfer would be a beneficial tool for the treatment of vascular diseases, such as postangioplasty restenosis, postbypass atherosclerosis, peripheral atherosclerotic disease, stenosis of vascular prosthesis anastomoses and thrombus formation. 8,13 Thus, there is a clear need to develop efficient nonviral gene transfer techniques for cardiovascular applications in vivo. In most conditions only a temporary expression of the transfected gene will be required to achieve a beneficial biological effect.…”

Eight-year safety follow-up of coronary artery disease patients after local intracoronary VEGF gene transfer

“…It is also a cytoprotective and anti-apoptotic factor leading to the inhibition of neointimal growth during vascular damage, and inducing angiogenesis especially in ischaemic tissues. [1][2][3][4][5][6][7] Therapeutic angiogenesis and inhibition of restenosis were the first targets of VEGF gene therapy. 2,5,7,8 The VEGF family consists of several members: VEGF (also called VEGF-A), VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F and placental growth factor.…”