Vascular endothelial growth factor blockade promotes the transition from compensatory cardiac hypertrophy to failure in response to pressure overload

Abstract

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.

Figure 1

Treatment with VEGF receptor decoy decreases the coronary vascular bed in hearts subjected to TAC. (A) TAC leads to an increase in VEGF-A transcript expression. (B) Representative images of TRITC-conjugated BS-1 lectin stained heart sections. Scale bars: 50 0 µm. (C) Quantitative analysis of capillary/myocyte ratio in Ad-cont– or Ad-Flk–treated mice at 2 weeks after sham operation or TAC. (D) Quantitative analysis of capillary density in Ad-cont– or Ad-Flk–treated mice 2 weeks after sham operation or TAC. Results are presented as mean±SEM (n=4 to 6 each). *P<0.05. #P<0.05 vs Ad-cont with sham.

Figure 2

Treatment with VEGF receptor decoy attenuates pressure overload induced cardiac hypertrophy in hearts subjected to TAC. (A) Heart weight/body weight ratio in Ad-cont– or Ad-Flk–treated mice 2 weeks after sham operation or TAC. *P<0.05. (B) Representative images of wheat germ agglutinin (WGA)-stained heart sections. Scale bars: 50 µm. (C) Quantitative analysis of cardiac myocyte cross-sectional area in Ad-cont– or Ad-Flk–treated mice 2 weeks after sham operation or TAC. Data were obtained from analysis of WGA-stained heart sections. Results are presented as mean±SEM (n=4 to 6 each). *P<0.05. #P<0.05 vs Ad-cont with sham.

Figure 3

VEGF receptor decoy promotes LV dilatation and contractile dysfunction in hearts subjected to TAC. (A) Representative M-mode echocardiogram for Ad-cont–or Ad-Flk–treated mice 2 weeks after sham operation or TAC. (B through E) Posterior wall thickness (PW), LVED dimension (LVEDd), %FS, and LVED pressure, respectively, in Ad-cont– or Ad-Flk–treated mice 2 weeks after sham operation or TAC. Results are presented as mean±SEM (n=4 to 6 each). *P<0.05. #P<0.05 vs Ad-cont with sham.

Figure 4

VEGF receptor decoy treatment promotes pathological cardiac remodeling in hearts. (A) Representative images of Masson’s trichrome (MT) staining of heart sections. Scale bars: 50 µm. (B) Quantitative analysis of myocardial interstitial fibrosis in Ad-cont– or Ad-Flk–treated mice 2 weeks after sham operation or TAC. (C) Collagen III mRNA expression in Ad-cont– or Ad-Flk–treated mice 2 weeks after sham operation or TAC. (D) Atrial natriuretic peptide (ANP) mRNA expression in Ad-cont– or Ad-Flk–treated mice 2 weeks after sham operation or TAC. Results are presented as mean±SEM (n=4 to 6 each). *P<0.05. #P<0.05 vs Ad-cont with sham.