HIF2α–arginase axis is essential for the development of pulmonary hypertension

Abstract

Hypoxic pulmonary vasoconstriction is correlated with pulmonary vascular remodeling. The hypoxia-inducible transcription factors (HIFs) HIF-1α and HIF-2α are known to contribute to the process of hypoxic pulmonary vascular remodeling; however, the specific role of pulmonary endothelial HIF expression in this process, and in the physiological process of vasoconstriction in response to hypoxia, remains unclear. Here we show that pulmonary endothelial HIF-2α is a critical regulator of hypoxia-induced pulmonary arterial hypertension. The rise in right ventricular systolic pressure (RVSP) normally observed following chronic hypoxic exposure was absent in mice with pulmonary endothelial HIF-2α deletion. The RVSP of mice lacking HIF-2α in pulmonary endothelium after exposure to hypoxia was not significantly different from normoxic WT mice and much lower than the RVSP values seen in WT littermate controls and mice with pulmonary endothelial deletion of HIF-1α exposed to hypoxia. Endothelial HIF-2α deletion also protected mice from hypoxia remodeling. Pulmonary endothelial deletion of arginase-1, a downstream target of HIF-2α, likewise attenuated many of the pathophysiological symptoms associated with hypoxic pulmonary hypertension. We propose a mechanism whereby chronic hypoxia enhances HIF-2α stability, which causes increased arginase expression and dysregulates normal vascular NO homeostasis. These data offer new insight into the role of pulmonary endothelial HIF-2α in regulating the pulmonary vascular response to hypoxia.A lveolar hypoxia affects vascular flow in the pulmonary vascular bed via an immediate vasoconstrictor response (hypoxic pulmonary vasoconstriction, or HPV) (1). This reduces perfusion of regions of the lung with lowered levels of airflow (2). In conditions including chronic obstructive pulmonary disease (3), idiopathic pulmonary fibrosis (4), and at high altitude (5), HPV probably contributes to persistent increases in pulmonary arterial pressures. This in turn is correlated with reduced plasticity of the vascular bed, sustained pulmonary vascular remodeling, and, ultimately, debilitating right ventricular hypertrophy (RVH) and failure (2).The hypoxia-inducible factors (HIFs) are transcription factors and key regulators of the molecular response to hypoxia. The targets of HIFs include genes controlling vascularization, cellular proliferation, migration, and metabolism (6-11). A wellcharacterized animal model of hypoxia-induced pulmonary hypertension involves exposure to chronic hypoxia (CH), typically 10-12% inspired oxygen. This results in extensive vascular remodeling, marked pulmonary hypertension and RVH over a period of a few weeks. Exposure to CH in rodents results in vasoconstriction and a pattern of vascular remodeling that is reminiscent of humans with hypoxia-associated pulmonary hypertension (12, 13).Mice that are hemizygous for either of the HIF isoforms, HIF-1α (14) or HIF-2α (15), have been shown to have attenuated pulmonary vascular remodeling following experimental CH. Conditional de...

Pulmonary hypertension in ARDS: inflammation matters!

“…Downstream, HIF-1α induces macrophage release of tumour necrosis factor-α, IL-1β and vascular endothelial growth factor 22. This is likely to contribute to the acute pulmonary vasoactive effects described in this paper, as well as more chronic effects on pulmonary vascular cell proliferation with the onset of hypoxic vascular remodelling 23. In terms of relevance for sphingolipids, studies in hypoxic mouse myocardium suggest the conversion of ceramide from its precursor is hypoxia-related;24 so, it is likely that HIF signalling is implicated in sphingolipid biology.…”

Endothelial cells and organ function: applications and implications of understanding unique and reciprocal remodelling

“…Oxygen sensing is essential for homeostasis and management of cellular energy, and one of the most important roles of the vasculature. It has been extensively described in the lung endothelium , which distinctly responds with vasoconstriction to drops in atmospheric oxygen, instead of the vasodilation observed in every other capillary network; The effect of O 2 availability has also been thoroughly studied in tumours, where the environment is hypoxic, perfusion is deficient, and angiogenic factors are abundant . The sensing and response to atmospheric oxygen levels are vital to mammalian energetic strategy, and the skin is a known key peripheral sensor that can alone modulate systemic blood flow .…”

“…These factors coordinate transcriptional programs downstream of their activation, following stabilization of their regulatory subunits with the most important being HIF‐1α and HIF‐2α . In EC, these are not only stress response factors, but act also, and primarily, as physiological regulators .…”

“…This essential function is at the heart of homeostasis , as it facilitates the adjustments needed to meet the demands of individual tissue types in specific circumstances. This includes normal physiological conditions, such as during exercise, and exposure to altitude or temperature oscillations , or in pathologies such as inflammation , cancer , ageing , degeneration or wound healing/tissue remodelling . Another point for consideration is the EC response during systemic therapy for chronic or acute conditions .…”

Discovery of a murine model of clinical PAH: Mission impossible?

“…A recent study also shows the superior role of endothelial HIF-2α versus endothelial HIF-1α in mediating chronic hypoxia-induced pulmonary vascular remodeling and PH. Mice lacking HIF-2α but not HIF-1α in lung endothelium ( L1 Cre) are completely resistant to chronic hypoxia-induced PH [40]. Chuvash polycythemia patients who have an R200W mutation in the von Hippel-Lindau (VHL) tumor suppressor protein are susceptible to development of PAH [41].…”