Endothelial Cell HIF-1α and HIF-2α Differentially Regulate Metastatic Success

Branco-Price, Cristina; Zhang, Na; Schnelle, Moritz; Evans, Colin E.; Katschinski, Dörthe M.; Ellies, Lesley G.; Johnson, Randall S.

doi:10.1016/j.ccr.2011.11.017

Cited by 151 publications

(150 citation statements)

References 61 publications

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“…Primary lung endothelial cell isolation. Primary endothelial cells were isolated and cultured from lungs of L1cre-HIF2α and WT mice, as previously described (25). Detailed methods are given in SI Methods.…”

Section: Methodsmentioning

confidence: 99%

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

Cowburn

Crosby

Macías

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

156

158

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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...

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Section: Methodsmentioning

confidence: 99%

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

Cowburn

Crosby

Macías

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

156

158

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“…For example, HIF-1a promotes cell cycle arrest, whereas HIF-2a promotes progression through the cell cycle, likely in a cell context-dependent manner (Keith et al 2012). In murine macrophages, keratinocytes, and endothelial cells, Hif-1a promotes NO production through activation of the inducible NO synthase (Nos2) gene, whereas Hif-2a inhibits NO production through the induction of the arginase (Arg) gene Branco-Price et al 2012;Cowburn et al 2013). Finally, Hif1a +/À mice display blunted respiratory responses to chronic hypoxia, while Hif2a +/À mice display exaggerated carotid body sensitivity to hypoxia ( Fig.…”

Section: The Hif Pathwaymentioning

confidence: 99%

Human high-altitude adaptation: forward genetics meets the HIF pathway

2014

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Humans have adapted to the chronic hypoxia of high altitude in several locations, and recent genome-wide studies have indicated a genetic basis. In some populations, genetic signatures have been identified in the hypoxia-inducible factor (HIF) pathway, which orchestrates the transcriptional response to hypoxia. In Tibetans, they have been found in the HIF2A (EPAS1) gene, which encodes for HIF-2α, and the prolyl hydroxylase domain protein 2 (PHD2, also known as EGLN1) gene, which encodes for one of its key regulators, PHD2. High-altitude adaptation may be due to multiple genes that act in concert with one another. Unraveling their mechanism of action can offer new therapeutic approaches toward treating common human diseases characterized by chronic hypoxia.

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“…However, despite the extensive homology it shares with HIF-1a, HIF-2a has its own physiological functions through induction of its unique target genes such as erythropoietin, octamer-binding transcription factor 4, and deltalike ligand 4 (18). Furthermore, studies of HIF-1a and HIF-2a in solid tumors have revealed their opposing roles in cell growth, energy metabolism, NO homeostasis, and other cell functions (18,19). These findings led us to test whether HIF-2a has functions that are distinct from those of HIF-1a in obese adipose tissue even though both HIF-1a and HIF-2a might be involved in angiogenesis in response to adipose tissue hypoxia.…”

mentioning

confidence: 99%

Macrophage HIF-2α Ameliorates Adipose Tissue Inflammation and Insulin Resistance in Obesity

Choe

Shin

et al. 2014

Diabetes

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In obesity, adipose tissue macrophages (ATMs) play a key role in mediating proinflammatory responses in the adipose tissue, which are associated with obesity-related metabolic complications. Recently, adipose tissue hypoxia has been implicated in the regulation of ATMs in obesity. However, the role of hypoxia-inducible factor (HIF)-2α, one of the major transcription factors induced by hypoxia, has not been fully elucidated in ATMs. In this study, we demonstrate that elevation of macrophage HIF-2α would attenuate adipose tissue inflammation and improve insulin resistance in obesity. In macrophages, overexpression of HIF-2α decreased nitric oxide production and suppressed expression of proinflammatory cytokines through induction of arginase 1. HIF-2α–overexpressing macrophages alleviated proinflammatory responses and improved insulin resistance in adipocytes. In contrast, knockdown of macrophage HIF-2α augmented palmitate-induced proinflammatory gene expression in adipocytes. Furthermore, compared with wild-type mice, Hif-2α heterozygous-null mice aggravated insulin resistance and adipose tissue inflammation with more M1-like ATMs upon high-fat diet (HFD). Moreover, glucose intolerance in HFD-fed Hif-2α heterozygous-null mice was relieved by macrophage depletion with clodronate treatment, implying that increase of proinflammatory ATMs is responsible for insulin resistance by haplodeficiency of Hif-2α upon HFD. Taken together, these data suggest that macrophage HIF-2α would counteract the proinflammatory responses to relieve obesity-induced insulin resistance in adipose tissue.

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Endothelial Cell HIF-1α and HIF-2α Differentially Regulate Metastatic Success

Cited by 151 publications

References 61 publications

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

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

Human high-altitude adaptation: forward genetics meets the HIF pathway

Macrophage HIF-2α Ameliorates Adipose Tissue Inflammation and Insulin Resistance in Obesity

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