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Effects of coronary artery disease on expression and microvascular response to VEGF
1Division of Cardiothoracic Surgery, Department of Surgery, Department of Medicine of Beth Israel-Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Insights
Coronary artery disease (CAD) impairs microvascular responses to vascular endothelial growth factor (VEGF), despite normal receptor expression. This suggests reduced nitric oxide release contributes to impaired vasodilation in CAD patients.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Endothelial Function
Background:
- Coronary artery disease (CAD) affects microvascular function.
- Vascular Endothelial Growth Factor (VEGF) plays a role in vasodilation.
- The impact of CAD on VEGF-mediated microvascular responses is not fully understood.
Purpose of the Study:
- To investigate the effects of CAD on human coronary microvascular responses to VEGF.
- To examine alterations in myocardial expression of VEGF and its receptors (flk-1, flt-1) in CAD.
- To explore the role of nitric oxide (NO) in VEGF-mediated responses in CAD.
Main Methods:
- In vitro video microscopy of human coronary microvessels from 48 patients.
- Assessment of VEGF and receptor expression using Northern analysis of total mRNA.
- Analysis of constitutive nitric oxide synthase (cNOS) and inducible nitric oxide synthase (iNOS) expression via RT-PCR.
Main Results:
- VEGF and hepatocyte growth factor (HGF) induced potent microvessel relaxations.
- These relaxations were significantly reduced in microvessels from CAD patients and inhibited by NG-nitro-L-arginine and genistein.
- VEGF, its receptors, cNOS, and iNOS expression levels were not altered in CAD patients.
Conclusions:
- VEGF and HGF mediate nitric oxide release via tyrosine kinase receptor activation.
- CAD is associated with diminished vascular responses to VEGF and HGF, independent of receptor expression or generalized endothelial dysfunction.
- Findings suggest potential implications for VEGF-based therapies in patients with CAD risk factors.
Abstract:
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.