Angiogenic mechanisms of endothelialization of cardiovascular implants: a review of recent investigative strategies

Abstract

Both cardiovascular implants and therapeutic interventions on native arteries fail due to biologic responses occurring at the blood/prosthesis/arterial wall and tissue/prosthesis/arterial wall interfaces, resulting in the failure modes of thrombosis and myointimal hyperplasia. Systemic pharmacologic approaches including use of anti-coagulant and anti-platelet agents have significant untoward side effects and have not resulted in a dramatic impact on failure modes in many applications, including small diameter vascular grafts. Local delivery of therapeutic agents via surface attachment with defined release kinetics may alter thrombogenicity and/or myointimal hyperplasia. Therapeutic agents may include a spectrum of biologic agents from peptides to endothelial cells. Efficient attachment and release of these agents in biologically active form is dependent upon improved methods of surface modification. The intended action of the biologic agent may similarly be impacted by the surface and bulk characteristics of the underlying biomaterial. It is often assumed, without concrete data. that surface re-endothelialization may have a beneficial impact on both thrombogenicity and myointimal hyperplasia. New clinical data on endothelial cell seeding has been supportive. Spontaneous re-endothelialization may be stimulated via an induced directed angiogenesis resulting in trans-interstitial capillarization and surface endothelialization. Recent advances in therapeutic angiogenesis have suggested the power of angiogenic factors to induce neovascularization of ischemic tissue beds. These concepts have been used to surface modify prosthetic devices with either VEGF or FGF and both in vitro and animal data suggest a potent stimulation of surface re-endothelialization. Neither of these growth factors is likely to be ideal. VEGF is relatively endothelial cell specific but is a relatively weak endothelial cell mitogen. FGF-1 and FGF-2 are more potent mitogens but are less cell specific. Recent work has led to the generation of mutant growth factors via site-induced mutagenesis and results of several such FGF mutants on endothelial cell and smooth muscle cell proliferative response have been studied. The use of 'designer growth factors' on cardiovascular implants and on manipulated native vessels may have a significant positive impact on re-endothelialization and thereby on the failure modes of thrombosis and myointimal hyperplasia.