Increased vascularization VEGF and HIF-1 expression in myocardium of chronically anemic fetal sheep

In chronic fetal anemia there is an increase in cardiac mass and cardiac output that is sufficient to maintain systemic tissue oxygenation. Cardiac output increases by 50%, myocardial blood flow increases five fold and cardiac hypertrophy occurs as the heart/body weight ratio increases 30%. To investigate the role of hypoxia inducible factor-1, an activator of vascular endothelial growth factor transcription in coronary vascular growth we measured VEGF, HIF-1 and capillary morphometry in fetal sheep at ∼130 d gestation made chronically anemic by daily isovolemic hemorrhage for 6 d. Compared to controls the hematocrit was reduced from 353±1.5 to 14.8±0.7%. Minimal capillary diameter increased in both the left (3.9±0.1 vs 5.5±0.5μm) and right ventricle (4.5±0.1 vs 7.1±0.4μm, means±se, n=5). The intercapillary distance, decreased in both the left (7.3±0.5 vs 5.5±0.4μm) and right ventricle (8.1±0.2 vs 5.5±0.4μm) and capillary density increased in the right ventricle (8.7±0.4 vs 10.4±0.6 10³/mm²). Compared to controls, in extracts of anemic hearts, VEGF protein increased 4.5 fold (p<.001), VEGF mRNA increased 3.2 fold (p=.004), HIF-1α protein increased 3.8 fold (p=0.002), and HIF-1β protein increased 1.78 fold (p=.08, n=6). These results provide evidence for a molecular pathway by which anemia/hypoxia may increase coronary capillary growth.