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Influence of 2-Methoxyestradiol and Sex on Hypoxia-Induced Pulmonary Hypertension and Hypoxia-Inducible Factor-1-α.

ABSTRACT: Background Women are at greater risk of developing pulmonary arterial hypertension, with estrogen and its downstream metabolites playing a potential role in the pathogenesis of the disease. Hypoxia-inducible factor-1-α (HIF 1α) is a pro-proliferative mediator and may be involved in the development of human pulmonary arterial hypertension . The estrogen metabolite 2-methoxyestradiol (2 ME 2) has antiproliferative properties and is also an inhibitor of HIF 1α. Here, we examine sex differences in HIF 1α signaling in the rat and human pulmonary circulation and determine if 2 ME 2 can inhibit HIF 1α in vivo and in vitro. Methods and Results HIF 1α signaling was assessed in male and female distal human pulmonary artery smooth muscle cells ( hPASMC s), and the effects of 2 ME 2 were also studied in female hPASMC s. The in vivo effects of 2 ME 2 in the chronic hypoxic rat (male and female) model of pulmonary hypertension were also determined. Basal HIF 1α protein expression was higher in female hPASMC s compared with male. Both factor-inhibiting HIF and prolyl hydroxylase-2 (hydroxylates HIF leading to proteosomal degradation) protein levels were significantly lower in female hPASMC s when compared with males. In vivo, 2 ME 2 ablated hypoxia-induced pulmonary hypertension in male and female rats while decreasing protein expression of HIF 1α. 2 ME 2 reduced proliferation in hPASMC s and reduced basal protein expression of HIF 1α. Furthermore, 2 ME 2 caused apoptosis and significant disruption to the microtubule network. Conclusions Higher basal HIF 1α in female hPASMC s may increase susceptibility to developing pulmonary arterial hypertension . These data also demonstrate that the antiproliferative and therapeutic effects of 2 ME 2 in pulmonary hypertension may involve inhibition of HIF 1α and/or microtubular disruption in PASMC s.

SUBMITTER: Docherty CK

PROVIDER: S-EPMC6474940 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectivesHIF2α is of vital importance in the regulation of endothelial dysfunction, cell proliferation, migration, and pulmonary vascular remodeling in pulmonary hypertension. Our previous studies demonstrated that conditional and inducible deletion of HIF2α in mouse lung endothelial cells, dramatically protected the mice against vascular remodeling and the development of pulmonary arterial hypertension (PAH). Here, we provide a novel transcriptome insight into the impact of HIF2α in PAH pathogenesis and the potential to use HIF2α-mediated gene sets to differentiate PAH human subjects.MethodsUsing transcriptome data, we first tapped the value of the difference in gene expression profile between wild type (WT) and Hif2a knockdown (KD) cell lines. We considered the deregulated genes between WT and Hif2a-KD cells as HIF2α influenced genes. By examining the lung tissue transcriptome data set with nine controls and eight PAH patients, we evaluated the HIF2α regulatory network in PAH pathogenesis to further determine the identification ability of HIF2α-mediated gene sets in human PAH subjects. On the other hand, using peripheral blood mononuclear cells (PBMCs) transcriptome data from PAH patients and healthy controls, we further validated the potential of the HIF2α-mediated PBMC gene sets as a possible diagnostic tool for PAH. To verify the ability of HIF2α-mediated gene sets for the identification of PAH, endothelial cell-specific Phd2 knockout mice with spontaneous pulmonary hypertension were used for reverse validation experiments.Results19 identified GO biological process terms were significantly correlated with the genes down-regulated in Hif2a-KD cells, all of which are strongly related to the PAH pathogenesis. We further assessed the discriminative power of these HIF2α-mediated gene sets in PAH human subjects. We found that the expression profile of the HIF2α-mediated gene sets in lung tissues and PBMCs were differentiated both between controls and PAH patients. Further, a significant positive correlation was observed between hypoxia and Phd2 deficiency mediated gene set expression profiles. As expected, 7 of the 19 significantly down-regulated GO terms in Hif2a-KD cells were found to overlap with the up-regulated GO gene sets in Phd2 EC-/- mice compared to WT controls, suggesting opposing effects of HIF2α and PHD2 on PAH pathogenesis.ConclusionHIF2α-mediated gene sets may be used to differentiate pulmonary arterial hypertension.

Project description:BackgroundPulmonary arterial hypertension (PAH) is associated with oxidative stress and affects the survival and homing of transplanted mesenchymal stem cells (MSCs) as well as cytokine secretion by the MSCs, thereby altering their therapeutic potential. In this study, we preconditioned the MSCs with prostaglandin E1 (PGE1) and performed in vitro and in vivo cell experiments to evaluate the therapeutic effects of MSCs in rats with PAH.MethodsWe studied the relationship between PGE1 and vascular endothelial growth factor (VEGF) secretion, B-cell lymphoma 2 (Bcl-2) expression, and C-X-C chemokine receptor 4 (CXCR4) expression in MSCs and MSC apoptosis as well as migration through the hypoxia-inducible factor (HIF) pathway in vitro. The experimental rats were randomly divided into five groups: (I) control group, (II) monocrotaline (MCT) group, (III) MCT + non-preconditioned (Non-PC) MSC group, (IV) MCT + PGE1-preconditioned (PGE1-PC) MSC group, and (V) MCT+PGE1+YC-1-PCMSC group. We studied methane dicarboxylic aldehyde (MDA) levels, MSC homing to rat lungs, mean pulmonary artery pressure, pulmonary artery systolic pressure, right ventricular hypertrophy index, wall thickness index (%WT), and relative wall area index (%WA) of rat pulmonary arterioles.ResultsPreconditioning with PGE1 increased the protein levels of HIF-1 alpha (HIF-1α) in MSCs, which can reduce MSC apoptosis and increase the protein levels of CXCR4, MSC migration, and vascular endothelial growth factor secretion. Upon injection with PGE1-PCMSCs, the pulmonary artery systolic pressure, mean pulmonary artery pressure, right ventricular hypertrophy index, %WT, and %WA decreased in rats with PAH. PGE1-PCMSCs exhibited better therapeutic effects than non-PCMSCs. Interestingly, lificiguat (YC-1), an inhibitor of the HIF pathway, blocked the effects of PGE1 preconditioning.ConclusionsOur findings indicate that PGE1 modulates the properties of MSCs by regulating the HIF pathway, providing insights into the mechanism by which PGE1 preconditioning can be used to improve the therapeutic potential of MSCs in PAH.

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Influence of 2-Methoxyestradiol and Sex on Hypoxia-Induced Pulmonary Hypertension and Hypoxia-Inducible Factor-1-α.

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