Published online before print May 26, 2009, doi: 10.1161/CIRCULATIONAHA.108.823609
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(Circulation. 2009;119:2928-2935.)
© 2009 American Heart Association, Inc.
Vascular Medicine |
Vascular Regeneration by Local Growth Factor Release Is Self-Limited by Microvascular Clearance
From the Harvard–MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge (K.N.L., A.R.T., E.R.E.); Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Johns Hopkins School of Medicine, Baltimore, Md (C.-W.H.); Department of Anesthesiology and Pain Medicine, Caritas St Elizabeth’s Medical Center, Boston Mass (M.A.L.); Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge (A.H.); and Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (E.R.E.).
Correspondence to Kha N. Le, Division of Health Sciences and Technology, Massachusetts Institute of Technology, Room E25–442, 77 Massachusetts Ave, Cambridge, MA 02139. E-mail knle{at}mit.edu
Received September 23, 2008; accepted February 23, 2009.
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.
Methods and 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.