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 language | English (US) |
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Pages (from-to) | 983-995 |
Number of pages | 13 |
Journal | American journal of respiratory and critical care medicine |
Volume | 202 |
Issue number | 7 |
DOIs | |
State | Published - 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