Vascular regeneration by local growth factor release is self-limited by microvascular clearance.
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.
Le
Kha N
KN
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
Hwang
Chao-Wei
CW
Tzafriri
A Rami
AR
Lovich
Mark A
MA
Hayward
Alison
A
Edelman
Elazer R
ER
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
D005346:Fibroblast Growth Factors