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 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/mm(3)) 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.
Zheng
W
W
Department of Anatomy and Cell Biology and The Cardiovascular Center, University of Iowa, Iowa City, Iowa 52242, USA.
Brown
M D
MD
Brock
T A
TA
Bjercke
R J
RJ
Tomanek
R J
RJ
D000208:Acute Disease; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D000906:Antibodies / Q000494:pharmacology; D015152:Blotting, Northern; D015153:Blotting, Western; D001835:Body Weight; D001919:Bradycardia / Q000139:chemically induced / Q000503:physiopathology*; D002196:Capillaries / Q000737:chemistry / Q000502:physiology; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D003331:Coronary Vessels / Q000737:chemistry / Q000502:physiology; D016228:Endothelial Growth Factors / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D016222:Fibroblast Growth Factor 2 / Q000032:analysis / Q000235:genetics / Q000276:immunology; D015870:Gene Expression / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D008222:Lymphokines / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D008297:Male; D018919:Neovascularization, Physiologic / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016277:Ventricular Function, Left
D000889:Anti-Arrhythmia Agents; D000906:Antibodies; D016228:Endothelial Growth Factors; D008222:Lymphokines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; C022192:alinidine; D003000:Clonidine