Abstract
Cellular responses to oxygen fluctuations are largely mediated by hypoxia-inducible factors (HIFs). Upon inhalation, the first organ inspired oxygen comes into contact with is the lungs, but the understanding of the pulmonary HIF oxygen-sensing pathway is still limited. In this review we will focus on the role of HIF1α and HIF2α isoforms in lung responses to oxygen insufficiency. In particular, we will discuss novel findings regarding their role in the biology of smooth muscle cells and endothelial cells in the context of hypoxia-induced pulmonary vasoconstriction. Moreover, we will also discuss recent studies into HIF-dependent responses in the airway epithelium, which have been even less studied than the HIF-dependent vascular responses in the lungs. In summary, we will review the biological functions executed by HIF1 or HIF2 in the pulmonary vessels and epithelium to control lung responses to oxygen fluctuations as well as their pathological consequences in the hypoxic lung.
Highlights
The lungs are responsible for oxygen uptake and the pulmonary vascular responses that ensure adequate blood oxygenation in response to low oxygen tensions
This study proposes that HIF1 activity induces PDGF-B in endothelial cells that can impact on pulmonary artery smooth muscle cells (PASMCs) cells to promote KLF14-dependent PASMC expansion (Figure 1)
In this review we have focused on the HIF1 and HIF2-dependent responses that are confined to the pulmonary vascular bed and airway epithelium
Summary
The lungs are responsible for oxygen uptake and the pulmonary vascular responses that ensure adequate blood oxygenation in response to low oxygen tensions These responses can be initiated in acute conditions of hypoxia (seconds to minutes), involving mechanisms such as membrane depolarization and the influx of calcium into pulmonary artery smooth muscle cells (PASMCs), which leads to elevated pulmonary vascular tone in poorly oxygenated alveoli [1,2,3]. While the HIFβ subunit is stable, the stability of the HIFα subunits fluctuates in response to changes in oxygen tension through the prolyl 2-oxoglutarate-dependent. HIFα subunits can enter the nucleus where they heterodimerize with HIFβ subunits and bind to DNA at hypoxia response elements (HREs), thereby driving a HIF-dependent transcriptional program [11,12]. In this review we focus on recent in vivo studies that have shed new light on the role of HIF1α and HIF2α isoforms in the response of the pulmonary vascular and airway epithelium to oxygen fluctuations (hypoxia)
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