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

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