Bradycardia-induced coronary angiogenesis is dependent on vascular endothelial growth factor

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 upregul ated in response to low heart rate and consequential increased stroke volum e. Bradycardia was induced in rats by administering the bradycardic drug al inidine (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%, a nd 18.5% after 1, 2, and 3 weeks of treatment, respectively. Arterial press ure and cardiac output were unchanged. Left ventricular capillary length de nsity (mm/mm(3)) increased gradually with alinidine administration; a 15% i ncrease after 2 weeks and a 40% increase after 3 weeks of alinidine treatme nt were documented. Left ventricular weight, body weight, and their ratio w ere not significantly altered by alinidine treatment. After 1 week of treat ment, 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 week s and increased further after 3 weeks of treatment. Injection of VEGF-neutr alizing antibodies over a 2-week period completely blocked alinidine-stimul ated angiogenesis. In contrast, bFGF mRNA was not altered by alinidine trea tment. These data suggest that VEGF plays a key role in the angiogenic resp onse that occurs with chronic bradycardia. The mechanism underlying this VE GF-associated angiogenesis may be an increase in stretch due to enhanced di astolic filling.