Abstract 3311: Endothelial HIF1a Protects Against Pulmonary Hypertension
Background: HIF-1a transcriptionally regulates the expression of a substantial repertoire of genes whose products modulate vascular function and angiogenesis. We hypothesized that the endothelium plays an important role in sensing and response to hypoxia and ischemia and that HIF-1a is a key mediator.
Methods and Results: Endothelial specific HIF-1a (ecHIF-null) knockout mice were generated by crossing HIF-loxP+/+ and Tie2-Cre mice. The pulmonary response to 3 weeks of chronic hypoxia (10% O2) was evaluated by microcatheter hemodynamics, histology, and gene expression analysis. Concomitantly the murine hind limb ischemia model was employed to test the effect of endothelial HIF-1a on flow recovery, arteriogenesis, and angiogenesis. Interestingly, although ecHIF-null mice had no significant increase in pulmonary/right ventricular pressures under normoxia, the loss of endothelial HIF1a expression markedly increased susceptibility to the induction of pulmonary hypertension by hypoxia (right ventricular/PA pressure 46.1±5.1 ecHIF-null vs. 27.1±3.4 mmHg control littermates; p=0.009; n=12/group). This was accompanied by an increase in pulmonary vascular segemental thickness, demonstrating that vascular remodeling contributed to the phenotype. HIF-1a mRNA level in the whole lung was significantly down by 70% in ecHIF-null mice (p=0.028). Hypoxia induced significant increase of apelin expression by 42% in wild type control mice, but decrease by 24% in ecHIF-null mice (P<0.05). ECHIF-null mice also demonstrated a marked defect in recovery from hindlimb ischemia, with control littermate mice attaining 87±19% vs. 60±16% in the ecHIF-null mice (% of non-ischemic limb flow at 4 wks; p<0.005). Angiography and digital analysis revealed a significant reduction in collateral vessel formation in the ecHIF-null mice, consistent with a significant arteriogenic defect, and there was a reduction in capillary counts in the lower limb, consistent with a concomitant defect in angiogenesis.
Conclusions: Endothelial oxygen sensing via HIF1a plays a crucial role in defining vascular responses to hypoxia and ischemia.