title: Vascular regeneration by local growth factor release is self-limited by microvascular clearance.
abstract: BACKGROUND
  The challenge of angiogenesis science is that stable sustained vascular regeneration in humans has not been realized despite promising preclinical findings. We hypothesized that angiogenic therapies powerfully self-regulate by dynamically altering tissue characteristics. Induced neocapillaries increase drug clearance and limit tissue retention and subsequent angiogenesis even in the face of sustained delivery.
  
  
  RESULTS
  We quantified how capillary flow clears fibroblast growth factor after local epicardial delivery. Fibroblast growth factor spatial loading was significantly reduced with intact coronary perfusion. Penetration and retention decreased with transendothelial permeability, a trend diametrically opposite to intravascular delivery, in which factor delivery depends on vascular leak, but consistent with a continuum model of drug transport in perfused tissues. Model predictions of fibroblast growth factor sensitivity to manipulations of its diffusivity and transendothelial permeability were validated by conjugation to sucrose octasulfate. Induction of neocapillaries adds pharmacokinetic complexity. Sustained local fibroblast growth factor delivery in vivo produced a burst of neovascularization in ischemic myocardium but was followed by drug washout and a 5-fold decrease in fibroblast growth factor penetration depth.
  
  
  CONCLUSIONS
  The very efficacy of proangiogenic compounds enhances their clearance and abrogates their pharmacological benefit. This self-limiting property of angiogenesis may explain the failures of promising proangiogenic therapies.
authors.affiliation: Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Room E25-442, 77 Massachusetts Ave, Cambridge, MA 02139, USA. knle@mit.edu
authors.forename: Kha N
authors.initials: KN
authors.lastname: Le
authors.forename: Chao-Wei
authors.initials: CW
authors.lastname: Hwang
authors.forename: A Rami
authors.initials: AR
authors.lastname: Tzafriri
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lovich
authors.forename: Alison
authors.initials: A
authors.lastname: Hayward
authors.forename: Elazer R
authors.initials: ER
authors.lastname: Edelman
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D004058:Diffusion; D004730:Endothelium, Vascular; D005346:Fibroblast Growth Factors / Q000097:blood* / Q000378:metabolism; D007511:Ischemia; D008833:Microcirculation / Q000502:physiology*; D055806:Microvessels / Q000502:physiology*; D008962:Models, Theoretical; D018919:Neovascularization, Physiologic; D010599:Pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D005346:Fibroblast Growth Factors