Abstract 3642: Local Therapeutic Angiogenesis Is Limited by Microvascular Clearance

Abstract

Local growth factor (GF) delivery is an attractive mode of vascular regenerative therapy for ischemic tissues. Yet, local release of proangiogenic GFs does not produce a sustained angiogenic response in clinical trials. We hypothesize that angiogenic therapies are self-regulated by dynamically altering tissue transport characteristics. Induced neocapillaries increase drug clearance rates, limiting tissue drug levels and induced vessel growth. We examined the interdependence of FGF distribution and angiogenesis in the rabbit heart in vivo (Fig ). 35 S-FGF1 penetrated 0.6 mm into the myocardium within 48 hr of release from epicardial controlled release patches. Drug release remained constant and angiogenesis was achieved but peaked at day 8 and regressed by day 31, as neocapillary clearance induced rapid increase of GF washout. An ex-vivo perfused heart model supported this interpretation. FGF2 distributions followed linear diffusion with low diffusivity (0.02 μm 2 /s) and low tissue penetration in the absence of coronary flow. Flow restoration enhanced clearance, contracting FGF2 penetration −46%. Findings were explained by a diffusion-clearance model, with a clearance rate constant K = 1.15×10 −4 sec −1 . The validated model of myocardial GF transport was coupled to a model angiogenic response to provide an integrated computational framework for evaluating local angiogenic therapy (insert). Induced angiogenesis is a double-edged sword. Early release of angiogenic compounds stimulates neo-vascularization but the very efficacy of these compounds enhances their clearance and abrogates their pharmacologic benefit.