Abstract

RATIONALE: Endothelial injury may provoke emphysema, but molecular pathways of disease development require further discernment. Emphysema lungs exhibit decreased expression of hypoxia inducible factor-2alpha (HIF-2alpha)-regulated genes, and tobacco smoke decreases pulmonary HIF-2alpha levels. These findings suggest that decreased HIF-2alpha expression is important in the development of emphysema.OBJECTIVES: The objective of this study was to evaluate the roles of endothelial cell (EC) HIF-2alpha in the pathogenesis of emphysema in mice.METHODS: Mouse lungs were examined for emphysema following either the loss or overexpression of EC Hif-2alpha. Additionally, SU5416, a VEGFR2 inhibitor, was used to induce emphysema. Lungs were evaluated for hepatocyte growth factor (HGF), a protein involved in alveolar development and homeostasis. Patient emphysema lungs were measured for endothelial HIF-2alpha expression.MEASUREMENTS AND MAIN RESULTS: EC Hif-2alpha deletion resulted in emphysema, in association with fewer ECs and pericytes. Following SU5416 exposure, EC Hif-2alpha knockout mice developed more severe emphysema, whereas EC Hif-2alpha-overexpressing mice were protected. EC Hif-2alpha knockout mice demonstrated lower levels of HGF. Human emphysema lung samples exhibited reduced EC HIF-2alpha expression.CONCLUSIONS: Here, we demonstrate a unique, protective role for pulmonary endothelial HIF-2alpha and how decreased expression of this endogenous factor causes emphysema; its pivotal protective function is suggested by its ability to overcome VEGF antagonism. HIF-2alpha may maintain alveolar architecture by promoting vascular survival and associated HGF production. In summary, HIF-2alpha 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.

View details for DOI 10.1164/rccm.202001-0078OC

View details for PubMedID 32515984