Effects of L-arginine on fibroblast growth factor 2-induced angiogenesis in a model of endothelial dysfunction.
BACKGROUND
Nitric oxide availability, which is decreased in advanced coronary artery disease associated with endothelial dysfunction, is an important mediator of fibroblast growth factor-2 (FGF-2)-induced angiogenesis. This could explain the disappointing results of FGF-2 therapy in clinical trials despite promising preclinical studies. We examined the influence of L-arginine supplementation to FGF-2 therapy on myocardial microvascular reactivity and perfusion in a porcine model of endothelial dysfunction.


RESULTS
Eighteen pigs were fed either a normal (NORM, n=6) or high cholesterol diet, with (HICHOL-ARG, n=6) or without (HICHOL, n=6) L-arginine. All pigs underwent ameroid placement on the circumflex artery and 3 weeks later received surgical FGF-2 treatment. Four weeks after treatment, endothelial-dependent coronary microvascular responses and lateral myocardial perfusion were assessed. Endothelial cell density was determined by immunohistochemistry. FGF-2, fibroblast growth receptor-1, endothelial-derived nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and syndecan-4 levels were determined by immunoblotting. Pigs from the HICHOL group showed endothelial dysfunction in the circumflex territory, which was normalized by L-arginine supplementation. FGF-2 treatment was ineffective in the HICHOL group (circumflex/left anterior descending blood flow ratios: 1.01 (rest) and 1.01 (pace), after and before treatment). Addition of L-arginine improved myocardial perfusion in response to FGF-2 at rest (ratio 1.13, P=0.02 versus HICHOL) but not during pacing (ratio 0.94, P=NS), and was associated with increased protein levels of iNOS and eNOS.


CONCLUSIONS
L-arginine supplementation can partially restore the normal response to endothelium-dependent vasorelaxants and myocardial perfusion in response to FGF-2 treatment in a swine model of hypercholesterolemia-induced endothelial dysfunction. These findings suggest a role for L-arginine in combination with FGF-2 therapy for end-stage coronary artery disease.
Voisine
Pierre
P
Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. pierre.voisine@chg.ulaval.ca
Li
Jian
J
Bianchi
Cesario
C
Khan
Tanveer A
TA
Ruel
Marc
M
Xu
Shu-Hua
SH
Feng
Jun
J
Rosinberg
Audrey
A
Malik
Tamer
T
Nakai
Yasunari
Y
Sellke
Frank W
FW
D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001160:Arterioles / Q000187:drug effects / Q000503:physiopathology; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000601:surgery; D003326:Coronary Circulation / Q000187:drug effects; D004036:Diet, Atherogenic; D004343:Drug Implants; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008562:Membrane Glycoproteins / Q000032:analysis; D008833:Microcirculation / Q000187:drug effects; D023421:Models, Animal; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000032:analysis; D052250:Nitric Oxide Synthase Type III / Q000032:analysis; D011509:Proteoglycans / Q000032:analysis; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000032:analysis; D013552:Swine; D013556:Swine, Miniature; D053671:Syndecan-4
D043925:Angiogenesis Inducing Agents; D004343:Drug Implants; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D053671:Syndecan-4; D016222:Fibroblast Growth Factor 2; D009569:Nitric Oxide; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D051496:Receptor, Fibroblast Growth Factor, Type 1