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

Abstract

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

Endothelial Oxygen Sensing in Alveolar Maintenance

“…In this issue of the Journal, Pasupneti and colleagues (pp. 983-995) explore the role of HIF (hypoxia-inducible factor) in the pathogenesis and treatment of emphysema (1).…”

“…n inducible factor-2a antagonist in patients with previously treated advanced clear cell renal cell carcinoma. Acute respiratory distress syndrome (ARDS) is a heterogeneous clinical syndrome characterized by severe respiratory failure requiring mechanical ventilatory support for which there is no therapy and in which mortality remains approximately 40% (1,2). A recent important advance has been the subclassification of ARDS into subphenotypes that have potential prognostic and/or therapeutic significance.…”

“…They used an inducible form of genetic recombination to specifically knock out Hif-2α in the endothelial cells of adult mice, which then developed features of emphysema over the subsequent 14–28 days. This included evidence of pneumocyte apoptosis, airspace enlargement, and obstructive ventilatory failure, which were not observed in mice with conditional Hif-1α deletion, demonstrating a HIF-2–specific function in alveolar maintenance ( 1 ).…”

“…The mechanism of this process remains unclear, although the authors propose impaired paracrine signaling. Reduced expression of the mitogenic hormone HGF (hepatocyte growth factor) was noted in the lungs of Hif-2α deficient mice, suggesting this might act as an endothelial-derived growth factor supporting pneumocyte survival ( 1 ). Interestingly, HGF is also implicated in postpneumonectomy lung growth ( 12 ).…”

Revisiting the Role for HIF Stabilizers in Bronchopulmonary Dysplasia

“…Interestingly, a recent publication demonstrated that endothelial-targeted inactivation of Hif-2α induces emphysema, whereas its overexpression confers protection against emphysema ( 10 ). Together, these studies add to many others stressing that cell and molecular maintenance programs necessary for proper alveolar formation are required for maintenance of adult alveolar tissue ( 2 ).…”