Vascular Regeneration by Local Growth Factor Release Is Self-Limited by Microvascular Clearance

• DOI: 10.1161/circulationaha.108.823609
• Publication Date: 2009-05-27T02:24:15Z
• Authors: Kha N. Le; Chao-Wei Hwang; A. Rami Tzafriri; Mark A. Lovich; Alison Hayward; Elazer R. Edelman
• Keywords: Vascular permeability

The challenge of angiogenesis science is that stable sustained vascular regeneration in humans has not been realized despite promising preclinical findings. We hypothesized angiogenic therapies powerfully self-regulate by dynamically altering tissue characteristics. Induced neocapillaries increase drug clearance and limit retention subsequent even the face delivery.We quantified how capillary flow clears fibroblast growth factor after local epicardial delivery. Fibroblast spatial loading was significantly reduced with intact coronary perfusion. Penetration decreased transendothelial permeability, a trend diametrically opposite to intravascular delivery, which delivery depends on leak, but consistent continuum model transport perfused tissues. Model predictions sensitivity manipulations its diffusivity permeability were validated conjugation sucrose octasulfate. Induction adds pharmacokinetic complexity. Sustained vivo produced burst neovascularization ischemic myocardium followed washout 5-fold decrease penetration depth.The very efficacy proangiogenic compounds enhances their abrogates pharmacological benefit. This self-limiting property may explain failures therapies.