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J Thorac Cardiovasc Surg 2001;121:735-742
© 2001 The American Association for Thoracic Surgery

Surgery for Acquired Cardiovascular Disease

Expression of vascular endothelial growth factor and its receptors is increased, but microvascular relaxation is impaired in patients after acute myocardial ischemia

From Harvard Medical School^a and the Division of Cardiothoracic Surgery and Angiogenesis Research Center,^b Beth Israel Deaconess Medical Center, Boston, Mass.

Supported by grants HL46716, HL53793, and HL56993 from the National Institutes of Health.

Received for publication June 29, 2000. Revisions requested Aug 22, 2000; revisions received Sept 18, 2000. Accepted for publication Sept 20, 2000. Address for reprints: Frank W. Sellke, MD, Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, 110 Francis St, LMOB 2A, Boston, MA 02215 (E-mail: fsellke{at}caregroup.harvard.edu).

Abstract

Background: Vascular endothelial growth factor, a specific endothelial mitogen, plays an important role in myocardial angiogenesis. Previous work has demonstrated increased expression of vascular endothelial growth factor and its receptors in a rat myocardial infarction model, as well as in a pig model of chronic ischemia. The expression of vascular endothelial growth factor and other growth factors after acute myocardial ischemia in patients has not been examined. In this study we examined the expression of vascular endothelial growth factor and its receptors and the responsiveness of human atrial microvessels to vascular endothelial growth factor before and after acute ischemia.
Methods: Paired specimens of human atrial tissue were harvested before and after atrial devascularization (ligation) in 16 patients undergoing coronary bypass operations.
Results: The messenger RNA (reverse transcriptase–polymerase chain reaction) level of vascular endothelial growth factor and vascular endothelial growth factor receptor 1 were increased by 22.2% ± 4.2% and 30.7% ± 7.6%, respectively (P < .05), in the ischemic specimens as compared with the control specimens. Protein expression (Western blotting) of vascular endothelial growth factor and that of vascular endothelial growth factor receptor 1 also were increased significantly by 71.7% ± 27.8% and 68.2% ± 27.6%, respectively (P < .05). However, both RNA and protein expressions of another vascular endothelial growth factor receptor, vascular endothelial growth factor receptor 2, and fibroblast growth factor and fibroblast growth factor receptor 1 were unchanged. Reactivity of precontracted atrial vessels was examined with video microscopy. Vascular endothelial growth factor–induced (33.9% ± 2.4% vs 18.3% ± 2.8% in control and ischemic vessels, respectively; P < .05), fibroblast growth factor–induced (31.6% ± 3.2% vs 15.8% ± 4.1%, P < .05), and substance P–induced (84.5% ± 3.7% vs 54.3% ± 9.0%, P < .05) microvascular relaxations were decreased in ischemic samples and in the presence of N^Gnitro-L-arginine, whereas responses to sodium nitroprusside were unchanged (90.9% ± 2.2% vs 91.2% ± 2.0%).
Conclusions: This study suggests that acute myocardial ischemia in patients results in increased expression of vascular endothelial growth factor but not fibroblast growth factor and that the functional activity of vascular endothelial growth factor receptors and that of other growth factors may be impaired.

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