Vascular endothelial growth factor-B gene transfer prevents angiotensin II-induced diastolic dysfunction via proliferation and capillary dilatation in rats

Aims Heart growth and function are angiogenesis-dependent, but little is known concerning the effects of key regulators of angiogenesis on diastolic heart failure. Here, we tested the hypothesis that local vascular endothelial growth factor-B (VEGF-B) gene therapy prevents left ventricular diastolic dysfunction. Methods and results Rats were subjected to pressure overload by infusing angiotensin II (33.3 µg/kg/h) for 2 weeks using osmotic minipumps. Intramyocardial delivery of adenoviral vector expressing VEGF-B167A improved the angiotensin II-induced diastolic dysfunction compared with LacZ control virus. Local VEGF-B gene transfer increased the mean capillary area in the left ventricle in control and angiotensin II-infused animals, whereas the density of capillaries was not affected. Interestingly, significant increases were noted in Ki67+ proliferating cells, expression of interleukin1β, and c-kit+ cells in response to VEGF-B gene transfer. The increase in cardiac c-kit+ cells was not associated with an induction of stromal cell-derived factor 1α, suggesting no mobilization of cells from bone marrow. Also, the phosphatidylinositol 3-kinase/Akt pathway was activated. Conclusion VEGF-B gene transfer resulted in prevention of the angiotensin II-induced diastolic dysfunction associated with induction of the Akt pathway, increased proliferation and number of c-kit+ cells, as well as an increase in the capillary area in the left ventricle. VEGF-B may offer novel therapeutic possibilities for the prevention of the transition from compensated to decompensated cardiac hypertrophy and thereby for the treatment of heart failure.