Effects of coronary artery disease on expression and microvascular response to VEGF.
The effects of coronary artery disease (CAD) on human coronary microvascular responses to vascular endothelial growth factor (VEGF) and the alterations of the myocardial expressions of VEGF and its flk-1 and flt-1 receptors were examined in 48 patients. Microvascular studies were performed in vitro with video microscopy. The expressions of VEGF and its receptors were examined using Northern analysis of total mRNA, and the expressions of constitutive nitric oxide synthase (cNOS) and inducible nitric oxide synthase (iNOS) were examined by RT-PCR. VEGF and hepatocyte growth factor (HGF) caused potent relaxations of microvessels. These responses were reduced in the presence of NG-nitro-L-arginine and the tyrosine kinase inhibitor genistein or in microvessels from patients with CAD. Relaxations to substance P and sodium nitroprusside were similar in both groups. The substance P response was abolished in the presence of NG-nitro-L-arginine. The expression of VEGF and its receptors and the expression of cNOS and iNOS were not altered in patients with CAD. In conclusion, VEGF and HGF elicit the release of nitric oxide through activation of tyrosine kinase receptors. CAD is associated with reduced vascular responses to both VEGF and HGF; this is not likely due to a reduced expression of VEGF or flt-1 or flk-1 receptors and not due to a generalized endothelium dysfunction despite the presence of mild hypercholesterolemia in these patients with CAD. These findings may have important implications regarding the efficacy of endogenous and exogenous VEGF in patients with risk factor for CAD.
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Division of Cardiothoracic Surgery, Department of Surgery, Department of Medicine of Beth Israel-Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Li
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J
Li
J
J
Simons
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M
Sellke
F W
FW
D000244:Adenosine Diphosphate / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D001026:Coronary Artery Bypass; D003327:Coronary Disease / Q000235:genetics / Q000503:physiopathology* / Q000601:surgery; D016228:Endothelial Growth Factors / Q000235:genetics* / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D019833:Genistein / Q000494:pharmacology; D006325:Heart Atria; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008222:Lymphokines / Q000235:genetics* / Q000494:pharmacology*; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D018715:Microscopy, Video; D008875:Middle Aged; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D019335:Nitroarginine / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D017978:Receptors, Growth Factor / Q000235:genetics; D011975:Receptors, Mitogen / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors; D014664:Vasodilation / Q000187:drug effects
D016228:Endothelial Growth Factors; D008222:Lymphokines; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D011975:Receptors, Mitogen; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019335:Nitroarginine; D000244:Adenosine Diphosphate; D017228:Hepatocyte Growth Factor; D019833:Genistein; C496319:NOS2 protein, human; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1