Endothelial HIF-2α as a Key Endogenous Mediator Preventing Emphysema

<b>Rationale:</b> Endothelial injury may provoke emphysema, but molecular pathways of disease development require further discernment. Emphysematous lungs exhibit decreased expression of HIF-2α (hypoxia-inducible factor-2α)-regulated genes, and tobacco smoke decreases pulmonary HIF-2α concentrations. These findings suggest that decreased HIF-2α expression is important in the development of emphysema.<b>Objectives:</b> The objective of this study was to evaluate the roles of endothelial-cell (EC) HIF-2α in the pathogenesis of emphysema in mice.<b>Methods:</b> Mouse lungs were examined for emphysema after either the loss or the overexpression of EC <i>Hif-2α</i>. In addition, SU5416, a VEGFR2 inhibitor, was used to induce emphysema. Lungs were evaluated for HGF (hepatocyte growth factor), a protein involved in alveolar development and homeostasis. Lungs from patients with emphysema were measured for endothelial HIF-2α expression.<b>Measurements and Main Results:</b> EC <i>Hif-2α</i> deletion resulted in emphysema in association with fewer ECs and pericytes. After SU5416 exposure, EC <i>Hif-2α</i>-knockout mice developed more severe emphysema, whereas EC <i>Hif-2α</i>-overexpressing mice were protected. EC <i>Hif-2α</i>-knockout mice demonstrated lower levels of HGF. Human emphysema lung samples exhibited reduced EC HIF-2α expression.<b>Conclusions:</b> Here, we demonstrate a unique protective role for pulmonary endothelial HIF-2α and how decreased expression of this endogenous factor causes emphysema; its pivotal protective function is suggested by its ability to overcome VEGF antagonism. HIF-2α may maintain alveolar architecture by promoting vascular survival and associated HGF production. In summary, HIF-2α may be a key endogenous factor that prevents the development of emphysema, and its upregulation has the potential to foster lung health in at-risk patients.