Inhibition of the cardiac angiogenic response to exogenous vascular endothelial growth factor.
BACKGROUND
The angiogenic effects of vascular endothelial growth factor (VEGF) are mediated by the stimulation of endothelial nitric oxide synthase (eNOS) and nitric oxide release. Nitric oxide availability is decreased in patients with coronary disease, a possible explanation for the humble results of VEGF in clinical trials. We sought to examine the effects of exogenous VEGF in a model of endothelial dysfunction.


METHODS
Miniswine fed either a regular (N = 6, group NORM) or hypercholesterolemic diet (N = 6, HICHOL) underwent ameroid placement on the circumflex artery. Three weeks later, baseline myocardial perfusion was assessed by microsphere injections, and all pigs were treated with VEGF. Four weeks later, microsphere injections were repeated and the hearts harvested. Endothelial-dependent coronary microvascular reactivity, and VEGF and eNOS expression were assessed.


RESULTS
HICHOL pigs showed significant endothelial dysfunction in the ischemic territory. Post-treatment myocardial blood flow in the circumflex territory was significantly higher in the NORM compared to the HICHOL group. VEGF and eNOS levels were increased in the ischemic territory in the NORM group but decreased in the HICHOL group.


CONCLUSIONS
The cardiac angiogenic response to VEGF was markedly inhibited in a hypercholesterolemia-induced porcine model of endothelial dysfunction. Coronary endothelial dysfunction could be an obstacle to the efficacy of clinical angiogenesis protocols and a putative therapeutic target.
Divisions of Cardiothoracic Surgery and Cardiology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Pierre
P
Voisine
Cesario
C
Bianchi
Marc
M
Ruel
Tamer
T
Malik
Audrey
A
Rosinberg
Jun
J
Feng
Tanveer A
TA
Khan
Shu-Hua
SH
Xu
Jennifer
J
Sandmeyer
Roger J
RJ
Laham
Frank W
FW
Sellke
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D003326:Coronary Circulation / Q000187:drug effects*; D042783:Endothelial Cells / Q000166:cytology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000502:physiology; D052250:Nitric Oxide Synthase Type III; D040262:Receptors, Vascular Endothelial Growth Factor / Q000502:physiology; D013552:Swine; D013556:Swine, Miniature; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D040262:Receptors, Vascular Endothelial Growth Factor