Effects of neuropeptide Y on collateral development in a swine model of chronic myocardial ischemia.
We investigated the role of neuropeptide Y (NPY), abundant in the myocardial sympathetic nervous system and endothelial cells, in angiogenesis during chronic myocardial ischemia. Adult male Yorkshire swine underwent ameroid constrictor placement on the proximal left circumflex coronary artery. After 3 weeks, an osmotic pump was placed to deliver either placebo (control, n=8) or NPY(3-36) (NPY, n=8) to the collateral dependent region. Five weeks after pump placement, after cardiac catheterization and hemodynamic assessment, the heart was harvested for analysis. NPY treated animals demonstrated increased mean arterial pressures and improved left ventricular function (+dP/dt). Cardiac catheterization demonstrated a significant increase in the blush score in the NPY group (p<0.001). Blood flow to the ischemic myocardium was not different between groups at rest or during ventricular pacing. Immunohistochemical double staining for CD-31 and smooth muscle actin demonstrated an increase in capillary and arteriole formation in NPY treated animals (p=0.02 and p<0.001). Immunoblotting showed a significant upregulation of DPPIV (p=0.009) and NPY receptors 1 (p=0.008), 2 (p=0.02) and 5 (p=0.03) in the NPY treated group. Additionally, there was significant upregulation of VEGF (p=0.04), eNOS (p=0.014), phospho-eNOS (ser1177) (p=0.02), and PDGF (p<0.001) in NPY treated group. The anti-angiogenic factors endostatin and angiostatin were significantly decreased in NPY treated animals (endostatin, p=0.03; angiostatin, p=0.04). Exogenous NPY(3-36) resulted in improved myocardial function and increased angiogenesis and arteriogenesis by stimulating growth factor, pro-angiogenic receptor upregulation, and decreasing anti-angiogenic expression, but did not increase blood flow to the ischemic myocardium. NPY may act as a good adjunct to primary agents of therapeutic angiogenesis.
Robich
Michael P
MP
Department of Surgery, Division of Cardiothoracic Surgery, Cardiovascular Research Center, Warren Alpert School of Medicine, Brown University, Providence, RI, USA.
Matyal
Robina
R
Chu
Louis M
LM
Feng
Jun
J
Xu
Shu-Hua
SH
Laham
Roger J
RJ
Hess
Philip E
PE
Bianchi
Cesario
C
Sellke
Frank W
FW
D000818:Animals; D002908:Chronic Disease; D003097:Collateral Circulation / Q000187:drug effects*; D017023:Coronary Angiography; D004195:Disease Models, Animal; D006334:Heart Function Tests; D015151:Immunoblotting; D007150:Immunohistochemistry; D055806:Microvessels / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008954:Models, Biological; D017202:Myocardial Ischemia / Q000000981:diagnostic imaging / Q000503:physiopathology*; D009478:Neuropeptide Y / Q000494:pharmacology*; D010477:Perfusion; D034421:Sus scrofa
D009478:Neuropeptide Y
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