© 1999 American Heart Association, Inc.
Original Contribution |
Bradycardia-Induced Coronary Angiogenesis Is Dependent on Vascular Endothelial Growth Factor
From the Department of Anatomy and Cell Biology and The Cardiovascular Center, (W.Z., R.J.T.) University of Iowa, Iowa City, Iowa; The School of Sport and Exercise Science (M.D.B.), University of Birmingham, United Kingdom; and Department of Pharmacology (T.A.B., R.J.B.), Texas Biotechnology Corporation, Houston, Tex.
Correspondence to Robert J. Tomanek, PhD, Department of Anatomy and Cell Biology, Bowen Science Building, University of Iowa, Iowa City, IA 52242. E-mail robert-tomanek{at}uiowa.edu
Abstract—A marked coronary angiogenesis is known to occur with chronic bradycardia. We tested the hypothesis that vascular endothelial growth factor (VEGF), an endothelial cell mitogen and a major regulator of angiogenesis, is upregulated in response to low heart rate and consequential increased stroke volume. Bradycardia was induced in rats by administering the bradycardic drug alinidine (3 mg/kg body weight) twice daily. Heart rate decreased by 32% for 20 to 40 minutes after injection and was chronically reduced by 10%, 14%, and 18.5% after 1, 2, and 3 weeks of treatment, respectively. Arterial pressure and cardiac output were unchanged. Left ventricular capillary length density (mm/mm3) increased gradually with alinidine administration; a 15% increase after 2 weeks and a 40% increase after 3 weeks of alinidine treatment were documented. Left ventricular weight, body weight, and their ratio were not significantly altered by alinidine treatment. After 1 week of treatment, before an increase in capillary length density, VEGF mRNA increased >2-fold and then declined to control levels after 3 weeks of treatment. VEGF protein was higher in alinidine-treated rats than in controls after 2 weeks and increased further after 3 weeks of treatment. Injection of VEGF-neutralizing antibodies over a 2-week period completely blocked alinidine-stimulated angiogenesis. In contrast, bFGF mRNA was not altered by alinidine treatment. These data suggest that VEGF plays a key role in the angiogenic response that occurs with chronic bradycardia. The mechanism underlying this VEGF-associated angiogenesis may be an increase in stretch due to enhanced diastolic filling.
Key Words: angiogenesis • bradycardia • alinidine • vascular endothelial growth factor • basic fibroblast growth factor
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