Reendothelialization And Restenosis

The luminal endothelium bestows a crucial protective effect on the adult vessel. Loss of endothelial coverage promotes neointima growth in part potentially because of media exposure to circulating growth factors [31]. The rationale to accelerate the integrity of the endothelial monolayer after arterial injury, to reduce neointimal growth and subacute thrombosis, has been extensively explored for over a decade [24, 32-34]. VEGF and other powerful endothelial mitogens have primarily been used as tools to stimulate re-endothelialization; several complimentary experimental approaches have been used to test this hypothesis. Early studies in small animal models demonstrated that local administration of VEGF-A, VEGF-C and VEGF-D significantly reduced intimal thickening [35]. In agreement with that data, the study of Hutter et al. demonstrated that sequestration of exogenous and/or endogenous VEGF by VEGF-trap delayed re-endothelialization and dramatically increased neointima size in a murine model of arterial injury [24]. Transfection of VEGFR2 DNA in a porcine coronary stent model at the time of stenting also significantly attenuated intimal proliferation [36]. Endostatin, an EC-specific inhibitor also resulted in inhibition of re-endothelialization, together with a subsequent increase of neointima size [37]. These and other similar studies led to the hypothetical use of angiogenic growth factors to therapeutically abrogate vascular restenosis. However, in a porcine coronary angioplasty model, periadventitial delivery of VEGF-A165 plasmid resulted in a substantially increased EC proliferation index but no discernible difference in neointima formation, compared to controls [38]. Furthermore, the early results claiming vasculoprotective effects of VEGF-A, -C and -D gene transfer have not been reproduced in later studies using comparable animal models [18].

Acceleration of endothelial repair and prevention of restenosis has been successfully demonstrated by an intravenous infusion of endothelial progenitor cells (EPCs) [39] [40]. The natural homing ability of these cells to regions of vascular injury make them an attractive option to exploit therapeutically [41], although the mechanism of their action remains uncertain and highly controversial. EPC capture stents, which are coated with an anti-human CD34 monoclonal antibody, have been designed for use in patients. Within 1 hour of deployment, EPCs bind to the endoluminal surface of such stents, then proliferate and migrate to fill the intra strut spaces establishing a confluent, functional and vasculoprotective EC monolayer on the stented arterial segment [42].

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