Abstract 4832: VEGF-B Ameliorates Angiotensin II Induced Left Ventricular Diastolic Dysfunction via Proliferation and Capillary Dilatation
The vascular endothelial growth factor-A (VEGF-A) is a key regulator of angiogenesis in health and disease, whereas the precise role of its homologue VEGF-B remains unclear. Here we tested the hypothesis that local VEGF-B gene therapy can ameliorate left ventricular diastolic dysfunction. 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 angiotensin II diastolic dysfunction compared to LacZ control virus (at 2 weeks left ventricular isovolumic relaxation time, 27±1 vs. 21±2, P<0.01, ratio of the mitral inflow velocities (E/A ratio) 1.5±0.3 vs. 2.7±0.7, n=7–8/group). Local VEGF-B gene transfer slightly increased mean capillary area in the left ventricle in control (4.1 vs. 5.6 μm2, n=5) and angiotensin II infused animals (4.0 vs. 5.2 μm2, n=5), while the density of capillaries was not affected. Interestingly, significant increases was noted in Ki-67+ proliferating cardiomyocytes (0.6±0.2 vs. 1.0±0.1 cells/high power field, P<0.05, n=5), non-myocyte cells (25.3±5.0 vs. 36.0±12.8 cells/high power field, n=5), as well as in c-kit+ cardiac stem cells (1.8±0.6 vs. 5.3±1.3 cells/35 mm2, P<0.01, n=5) in the left ventricle in response to VEGF-B gene transfer in control and angiotensin II infused (0.1±0.0 vs. 0.3±0.1, 1.7±0.4 vs. 4.8±1.9 and 1.5±0.5 vs. 3.0±0.4, respectively, n=5 in all groups) rats. The increase in cardiac c-kit+ stem cells was not associated with an induction of stromal cell-derived factor 1α, indicating no mobilization of cells from bone marrow. Fibrosis or the rate of apoptosis was not altered by angiotensin II or VEGF-B. In summary, VEGF-B gene transfer resulted in amelioration of angiotensin II induced diastolic dysfunction associated with proliferation of cardiomyocytes, induction of cardiac c-kit+ stem cells and increase in capillary area in the ventricle. These insights may offer novel therapeutic possibilities for the treatment of heart failure and the transition from compensated to decompensated cardiac hypertrophy induced by pressure overload.