Reverse Remodelling of the Lung Vasculature after Hypoxia
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE183908 | GEO | 2022/09/01
REPOSITORIES: GEO
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Project description:Uncontrolled accumulation of pulmonary artery smooth muscle cells (PASMC) to the distal pulmonary arterioles (PAs) is one of the major characteristics of pulmonary hypertension (PH). Cellular senescence contributes to aging and lung diseases associated with PH and links to PH progression. However, the mechanism by which cellular senescence controls vascular remodeling in PH is not fully understood. The levels of senescence marker, p16INK4A and senescence-associated β-galactosidase (SA-β-gal) activity are higher in PA endothelial cells (ECs) isolated from idiopathic pulmonary arterial hypertension (IPAH) patients compared to those from healthy individuals. Hypoxia-induced accumulation of α-smooth muscle actin (αSMA)-positive cells to the PAs is attenuated in p16fl/fl-Cdh5(PAC)-CreERT2 (p16iΔEC) mice after tamoxifen induction. We have reported that endothelial TWIST1 mediates hypoxia-induced vascular remodeling by increasing platelet-derived growth factor (PDGFB) expression. Transcriptomic analyses of IPAH patient or hypoxia-induced mouse lung ECs reveal the alteration of senescence-related gene expression and their interaction with TWIST1. Knockdown of p16INK4A attenuates the expression of PDGFB and TWIST1 in IPAH patient PAECs or hypoxia-treated mouse lungs and suppresses accumulation of αSMA–positive cells to the supplemented ECs in the gel implanted on the mouse lungs. Hypoxia-treated mouse lung EC-derived exosomes stimulate DNA synthesis and migration of PASMCs in vitro and in the gel implanted on the mouse lungs, while p16iΔEC mouse lung EC-derived exosomes inhibit the effects. These results suggest that endothelial senescence controls αSMA–positive cell proliferation and migration in PH through TWIST1-PDGFB signaling.
2022-10-15 | PXD033549 | Pride
Project description:Uncontrolled accumulation of pulmonary artery smooth muscle cells (PASMC) to the non-muscularized distal pulmonary arterioles (PAs) is one of the major characteristics of pulmonary hypertension (PH). Cellular senescence contributes to aging and lung diseases associated with PH and links to PH progression. However, the mechanism by which cellular senescence controls vascular remodeling in PH is not fully understood. Here, we have demonstrated that endothelial senescence mediates PH pathology by increasing platelet-derived growth factor (PDGFB) expression. The levels of senescence markers p16INK4A and senescence-associated β-galactosidase (SA-β-gal) are higher in PA endothelial cells (ECs) isolated from IPAH patients compared to those from healthy individuals. Hypoxia-induced accumulation of α-smooth muscle actin (αSMA)-positive cells to the PAs is attenuated in p16INK4Afl/fl-Cdh5(PAC)-CreERT2 mice after tamoxifen induction. We have reported that endothelial TWIST1 mediates hypoxia-induced vascular remodeling by increasing PDGFB expression. Transcriptomic analyses of idiopathic pulmonary arterial hypertension (IPAH) patient lung ECs or hypoxia-induced mouse lung ECs reveal the alteration of senescence-related gene expression and interaction with TWIST1. Increases in the levels of PDGFB and TWIST1 in hypoxia-treated mouse lung ECs or IPAH patient lung ECs are attenuated by knocking down p16INK4A expression or treating with senolytic reagents. Knockdown of p16INK4A also suppresses accumulation of αSMA–positive cells to the supplemented ECs in the gel. Exosomes collected from hypoxia-treated mouse lung ECs stimulate SMC DNA synthesis and migration in vitro and in the gel implanted on the mouse lungs, while p16INK4A knockdown in ECs inhibits the effects. These results suggest that endothelial senescence controls αSMA–positive cell proliferation and migration in PH through TWIST1-PDGFB signaling.
2022-10-12 | GSE193272 | GEO
Project description:Chronic hypoxia induces pulmonary vascular remodeling and pulmonary hypertension (PH). While it is established that transcription factors, hypoxia-inducible factors (HIF-1α/HIF-2α) activate gene programs that drive hypoxia-induced PH, the mechanism of HIF-1/2 activation is less clear. Here, we report that carboxylterminus of Hsp70-interacting protein (CHIP or Stub1) modulates HIF-1α and HIF-2α transcription rather than reducing their stability. Knocking-down Stub1 reduced hypoxic activation of HIF-1α mRNA, protein, and activity while enhancing hypoxic induction of HIF-2α mRNA, protein, and target genes in pulmonary vascular cells. Mechanistically, CBP/p300-mediated acetylation of lysine (K287) inactivates the ubiquitin ligase activity of Stub1 and triggers its translocation from the cytoplasm into the nucleus. There, it recognizes the HIF promoter and hypoxia response elements (HREs) in target genes. Expression of Stub1-K287Q mutant (mimicking acetylation) enhanced hypoxia-induced HIF-1α expression, while acetyl-deficient Stub1-K287R mutant had the opposite effect on HIF-α but enhanced hypoxia-induced HIF-2α transcriptional activity. Endothelial-Stub1 transgenic mice tolerated chronic hypoxia better, had less pulmonary vascular remodeling, reduced pulmonary vascular resistance, and greater cardioprotection. Thus, Stub1 nuclear translocation enhances hypoxic induction of HIF-1α activity while suppressing deleterious effects of HIF-2α. These observations indicate that nuclear-Stub1 synergizes with HIF-1α to promote transcriptional responses and antagonizes HIF2α-driven PH in chronic hypoxia.
2023-04-01 | GSE221264 | GEO
Project description:Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disease that culminates in right heart failure. Vascular pathology in PH is characterized by pulmonary vasoconstriction and progressive vascular remodeling processes that affects all layers of the vascular wall (intima, media and adventitia).
2022-06-09 | GSE194080 | GEO
Project description:There is marked sexual dimorphism displayed in the onset and progression of pulmonary hypertension (PH). Females more commonly develop pulmonary arterial hypertension (PAH), however, females with PAH and other types of PH have better survival than males. Pulmonary microvascular endothelial cells play a crucial role in the pulmonary vascular remodelling and increased pulmonary vascular resistance of PH. Given this background, we hypothesized that there are sex differences in the pulmonary microvascular endothelium basally and in response to hypoxia that are independent of the sex hormone environment.
2024-01-03 | PXD046787 | Pride
Project description:Vascular remodeling is the process of structural alteration and cell rearrangement of blood vessels in response to injury and is the cause of many of the world's most afflicted cardiovascular conditions, including pulmonary arterial hypertension(PAH). Many studies have focused on the effects of vascular endothelial cells and smooth muscle cells(SMCs) during vascular remodeling, but pericytes, an indispensable cell population residing largely in capillaries, are ignored in this maladaptive process. Here we report that hypoxia-inducible factor 2α(HIF2α) expression is increased in human PAH patient lung tissues and HIF2α overexpressed pericytes result in greater contractility and an impaired endothelial-pericyte interaction. Using single-cell RNAseq and hypoxia-induced pulmonary hypertension(PH) models, we show HIF2α as a major molecular regulator for pericytes’ transformation into SMC-like cells. HIF2α overexpression in pericyte-selective mice exacerbate PH and right ventricular hypertrophy. Temporal cellular lineage tracing shows that HIF2α overexpressing reporter NG2+ cells (pericyte-selective) relocate from capillaries to arterioles and co-express SMA. This novel insight into the potential role of NG2+ pericytes in pulmonary vascular remodeling via HIF2α signaling suggests a potential drug target for PH.
2023-12-11 | GSE249461 | GEO
Project description:Pulmonary arterial hypertension (PAH) is a chronic progressive disease with significant morbidity and mortality. The disease is characterized by vascular remodeling that includes increased muscularization of distal blood vessels and vessel stiffening associated with changes in extracellular matrix deposition. In humans, chronic hypoxia causes PAH, and hypoxia-induced rodent models of PAH have been used for years to study the disease. With the development of single-cell RNA sequencing technology, it is now possible to examine hypoxia-dependent transcriptional changes in vivo at a cell-specific level. In this study, we used single-cell RNA sequencing to compare lungs from wild-type mice exposed to hypoxia for 28 days to normoxia-treated control mice. We additionally examined mice deficient for Notch3, a smooth muscle-enriched gene linked to PAH. Data analysis revealed that hypoxia promoted cell number changes in immune and endothelial cell types in the lung, activated the innate immunity pathway, and resulted in specific changes in gene expression in vascular cells. Surprisingly, we found limited differences in lungs from mice deficient for Notch3 compared to wild-type controls. These findings provide novel insight into the effects of chronic hypoxia exposure on gene expression and cell phenotypes in vivo and identify unique changes to cells of the vasculature.
2022-08-01 | GSE209738 | GEO
Project description:Rationale: Pulmonary arterial hypertension (PAH) is a devastating disease characterized by obliterative vascular remodeling and persistent increase of vascular resistance, leading to right heart failure and premature death. Understanding the cellular and molecular mechanisms will help develop novel therapeutic approaches for PAH patients. Objectives: To determine whether upregulation of fatty-acid binding protein 4 and 5 (FABP4/5) is critical in pathogenesis of PAH. Methods: FABP4/5 expression was examined in pulmonary arterial endothelial cells (PAECs) and lung tissues from patients with idiopathic PAH and pulmonary hypertension (PH) rat models. Plasma proteome analysis was performed in human PAH samples. Echocardiography, hemodynamics, histology, and immunostaining were performed to evaluate the lung and heart PH phenotypes in Egln1Tie2Cre (CKO) mice and Egln1Tie2Cre/Fabp4-5-/- (TKO) mice. Measurement and Main Results: Both FABP4 and FABP5 were highly induced in ECs of CKO mice and PAECs from IPAH patients, and in whole lungs of PH rats. Plasma levels of FABP4/5 were upregulated in IPAH patients and directly correlated with severity of hemodynamics and biochemical parameters. Genetic deletion of both Fabp4 and 5 in CKO mice caused a reduction of right ventricular systolic pressure (RVSP) and RV hypertrophy, attenuated pulmonary vascular remodeling and prevented the right heart failure. Fabp4/5 deletion also normalized EC glycolysis, reduced ROS and HIF-2a expression, and decreased aberrant EC proliferation in CKO lungs. Conclusions: PH causes aberrant expression of FABP4/5 in pulmonary ECs which leads to enhanced EC glycolysis and hyperproliferation, contributing to the accumulation of arterial ECs and vascular remodeling and exacerbating the disease.
2024-08-02 | GSE261445 | GEO
Project description:As the critical step of pathogenesis during hypoxic pulmonary arterial hypertension (PAH) vascular remodeling is closely associated with pulmonary arterial smooth muscle cell (PASMC) alterations induced by hypoxia that include persistent vasoconstriction, abnormal proliferation and PASMC resistance to apoptosis. Quercetin is a flavonoid compound extracted from green plants that inhibits proliferation, induces apoptosis, arrests the cell cycle, and rescues the constriction of PASMCs, but the underlying mechanisms remain poorly understood. In this study, we used a commercial Agilent Whole Rat Genome Oligo Microarray to determine the overall transcriptional response of PASMCs in response to exposure to hypoxia and the optimal concentration of quercetin. Hypoxia induced the upregulation of 1694 genes and the downregulation of 2091 genes compared with the normoxia group. Quercetin treatment resulted in 1790 upregulated genes and 1450 downregulated genes. Quercetin is known to cause differential expression of several of these genes that are known to promote proliferation, induce apoptosis (Cycs, Ppp3ca, Prkar2b, Akt3, Ppp3cc, Il1rap, Ntrk1), arrest the cell cycle (Chek2, Cdkn1c, Gadd45b, Stag2, Anapc7, Orc1, Ccne1, Myc3, Skp1, Espl1, Cdc45, Mcm4), and rescue PASMC constriction (Ramp1, Ramp3, Adcy5, Gnas, Prkcd, Itpr3, Adra1d, Calm1, Npr1, Avpr1a, Ednra, Adcy8). Real-time quantitative RT-PCR was performed to verify the microarray results. In conclusion, quercetin altered the expression profile of many genes regulated by hypoxia in PASMCs, which helps to further explore the mechanism of the effects of quercetin treatment on hypoxic PAH.
2015-08-20 | GSE72181 | GEO
Project description:Pulmonary hypertension (PH) is a common complication of systemic sclerosis (SSc) and a leading cause of mortality among patients with this disease. PH can also occur as an idiopathic condition (idiopathic pulmonary arterial hypertension, iPAH). We sought to investigate the transcriptomic alterations in PH vascular populations to understand cellular mechanisms underlying pathobiology of systemic sclerosis associated and idiopathic pulmonary hypertension.
2024-06-07 | GSE244781 | GEO