Endothelial HIF-2a as a key endogenous mediator preventing emphysema

Shravani Pasupneti, Wen Tian, Allen B. Tu, Petra Dahms, Eric Granucci, Aneta Gandjeva, Menglan Xiang, Eugene C. Butcher, Gregg L. Semenza, Rubin M. Tuder, Xinguo Jiang, Mark R. Nicolls

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)983-995
Number of pages13
JournalAmerican journal of respiratory and critical care medicine
Volume202
Issue number7
DOIs
StatePublished - Oct 1 2020

Keywords

  • Emphysema
  • Hepatocyte growth factor
  • Hypoxia-inducible factor-2a

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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