Vascular endothelial growth factor blockade promotes the transition from compensatory cardiac hypertrophy to failure in response to pressure overload.
Cardiac hypertrophy is associated with upregulation of vascular endothelial growth factor (VEGF) in the myocardium. Here, we evaluated the effects of a decoy VEGF receptor on heart morphology and function to a murine model of pressure overload hypertrophy. Mice were administered adenoviral vector encoding a decoy VEGF receptor (Ad-Flk), and their hearts were subjected to pressure overload by transverse aortic constriction (TAC). Treatment with Ad-Flk led to a net reduction in capillary density in hearts subjected to TAC. Ad-Flk also led to a reduction in TAC-induced cardiac hypertrophy and promoted left ventricle dilatation and a loss in contractile function. Treatment with Ad-Flk markedly increased myocardial fibrosis and collagen gene upregulation. In contrast, Ad-Flk had no effect on any of these parameters in sham-treated mice. Administration of a VEGF trap reagent diminished pressure overload cardiac hypertrophy and promoted the progression to heart failure but had no effect on sham-treated animals. These findings suggest that VEGF is required to maintain myocardial capillary density and that reductions in the vascular bed are associated with the transition from compensatory hypertrophy to failure.
Izumiya
Yasuhiro
Y
Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA.
Shiojima
Ichiro
I
Sato
Kaori
K
Sawyer
Douglas B
DB
Colucci
Wilson S
WS
Walsh
Kenneth
K
D000222:Adaptation, Physiological; D000818:Animals; D001011:Aorta; D002196:Capillaries / Q000473:pathology; D002303:Cardiac Output, Low / Q000209:etiology*; D006332:Cardiomegaly / Q000150:complications* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D003094:Collagen / Q000378:metabolism; D003250:Constriction; D003326:Coronary Circulation; D004452:Echocardiography; D005355:Fibrosis; D018014:Gene Transfer Techniques; D006973:Hypertension / Q000150:complications* / Q000503:physiopathology; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D020257:Ventricular Remodeling
D007141:Immunoglobulin Fc Fragments; D042461:Vascular Endothelial Growth Factor A; D003094:Collagen; D040301:Vascular Endothelial Growth Factor Receptor-2