RNA sequencing of lung tissue from wildtype and hypoxia-induced pulmonary hypertension/hypoxia-induced pulmonary hypertension mice under aerobic exercise conditions
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE272157 | GEO | 2025/12/31
REPOSITORIES: GEO
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Project description:Here we investigated the protein composition of the main pulmonary artery (MPA), distal pulmonary arteries (DPA) distal whole lung (DWL) of early stage hypoxia (using a neonatal bovine calf model) and late stage hypoxia (using adult steers with hypoxia-induced PH) using high resolution mass spectrometry. Compartment-resolved analysis allowed for quantitative measurements of proteins from cellular, soluble ECM and insoluble ECM fractions
2022-10-06 | MSV000090482 | MassIVE
Project description:Right ventricular (RV) failure is the major determinant of outcome in pulmonary hypertension (PH). Calves exposed to 2-wks environmental hypoxia develop severe PH and unlike rodents, chronic hypoxia-induced PH in this species can lead to right heart failure. We therefore sought to examine the molecular and structural changes in the RV in calves with hypoxia-induced PH, hypothesizing that we could identify mechanisms underlying compensated physiological function in the face of developing severe PH. Calves were exposed to 14d of hypobaric hypoxia (PB=430 mm Hg, equivalent to 4570m elevation, n=29) or ambient normoxia (1525m, n=25). Cardiopulmonary function was evaluated by right heart catheterization and pressure volume loops. Molecular and cellular determinants of RV remodeling were analyzed by cDNA microarrays, RealTime PCR, proteomics and immunochemistry. Hypoxic exposure induced robust PH, with increased RV contractile performance and preserved cardiac output, yet evidence of dysregulated RV-pulmonary artery mechanical coupling consistent with advanced PH. Analysis of gene expression revealed cellular processes associated with structural remodeling, cell signaling, and survival. We further identified specific clusters of gene expression associated with (i) hypertrophic gene expression and pro-survival mechanotransduction through YAP-TAZ signaling, (ii) ECM remodeling, (iii) inflammatory cell activation and (iv) angiogenesis. A potential transcriptomic signature of cardiac fibroblasts in RV remodeling was detected. Proteomic and immunohistochemical analysis confirmed RV myocyte hypertrophy, together with localization of ECM remodeling, inflammatory cell activation, and endothelial cell proliferation within the RV interstitium. In conclusion, hypoxia and hemodynamic load initiate coordinated processes of protective and compensatory RV remodeling to withstand the progression of PH.
2023-03-20 | GSE217438 | GEO
Project description:Pulmonary hypertension (PH) is a chronic and progressive disease with significant morbidity and mortality. It is characterized by remodeled pulmonary vessels associated with perivascular and intravascular accumulation of inflammatory cells. While there is compelling evidence that bone marrow-derived cells, such as macrophages and T cells, cluster in the vicinity of pulmonary vascular lesions in humans and that they contribute to PH development in different animal models, the role of dendritic cells in PH is less clear. Dendritic cells' involvement in PH is likely since they are responsible for coordinating innate and adaptive immune responses. We hypothesized that dendritic cells drive hypoxic PH. We demonstrate that a classical dendritic cell (cDC) subset (cDC2) is increased and activated in wild-type mouse lungs after hypoxia exposure. We observe significant protection after the depletion of cDCs in ZBTB46 DTR chimera mice before hypoxia exposure and after established hypoxic PH. In addition, we find that cDC depletion is associated with a reduced number of two macrophage subsets in the lung (FolR2+ MHCII+ CCR2+ and FolR2+ MHCII+ CCR2-). We found that depleting cDC2s, but not cDC1s, was protective against hypoxic PH. Finally, proof-of-concept studies in human lungs show increased perivascular cDC2s in patients with Idiopathic Pulmonary Arterial Hypertension (IPAH). Our data points to an essential role of cDCs in the pathophysiology of PH.
2024-08-24 | GSE256348 | GEO
Project description:The precise origin of newly formed alpha smooth muscle actin-positive (ACTA2+) cells appearing in non-muscularized vessels in the context of pulmonary hypertension (PH) is still debatable, although it is believed that they predominantly derive from pre-existing vascular smooth muscle cells (VSMCs). Here, Gli1Cre-ERT2; tdTomatoflox mice were used to lineage-trace GLI1+ cells in the context of PH using two independent models of vascular remodeling (VR) and reverse remodeling (RR): hypoxia and cigarette-smoke exposure (SE). Hemodynamic measurements, right ventricular hypertrophy assessment, flow cytometry, and histological analysis of thick lung sections followed by state-of-the-art 3D reconstruction and quantification using Imaris software were used to investigate the contribution of GLI1+ cells to neo-muscularization of the pulmonary vasculature. The data show that GLI1+ cells are abundant around distal, non-muscularized, vessels during steady state, and that this lineage contributes to around 50% of newly formed ACTA2+ cell around these normally non-muscularized vessels. During RR, cells derived from the GLI1+ lineage are largely cleared in parallel to the reversal of muscularization. Partial ablation of GLI1+ cells greatly prevented VR in response to hypoxia and attenuated the increase in RVSP and right heart hypertrophy. Single-cell RNA sequencing (scRNA-seq) on sorted lineage-labeled GLI1+ cells revealed an Acta2high fraction of cells with pathways in cancer and MAPK signaling as potential players in reprogramming these cells during VR. Analysis of human lung-derived material suggests that GLI1 signaling is overactivated in both Group 1 and Group 3 PH and can promote proliferation and myogenic differentiation. Our data highlight GLI1+ cells as an alternative cellular source of VSMCs in PH and suggest that these cells and the associated signaling pathways represent an important therapeutic target for further studies.
2024-05-14 | GSE260788 | GEO
Project description:Pulmonary hypertension (PH) is a progressive disease with a high mortality rate, usually as a result of right heart failure. The pulmonary vasculature in PH is characterized by remodeling and stiffening, potentially with luminal obstruction, driven by enhanced cell proliferation/survival versus cell death, chronic inflammation, and altered extracellular matrix (ECM), with an increase in vascular fibrosis. Given the poorly understood biochemical nature of pulmonary vascular remodeling, we evaluated the ECM and ECM-associated protein composition of the main pulmonary artery (MPA), distal pulmonary arteries (DPA) distal whole lung (DWL) of acute hypoxia-driven PH (in a young bovine calf model) using high-resolution mass spectrometry. Significant differences in the proteomic signatures were observed in the three vascular/tissue sites. Alterations included a strong immune response and wound repair signature including several proteins from the coagulation cascade and markers of a provisional matrix. These findings support a role for disease propagation that proceeds through a wound-healing trajectory with a strong hemostasis and provision matrix in the MPA, to a more destructive remodeling with higher turnover in the most distal capillaries. This data provides insight into short-term remodeling that results in robust biomechanical manifestation of PH and initiates a resolvable disease trajectory when hypoxic insult is removed.
2025-12-08 | PXD046794 | Pride
Project description:Pulmonary hypertension (PH) is an incurable right heart failure disease. Parathyroid hormone (PTH) is secreted from the parathyroid gland and plays a crucial role in calcium homeostasis. PTH also acts on the cardiovascular system and affects cardiovascular prognosis. We assessed whether the regulation of PTH affected PH in a hypoxia (Hx)-induced PH mouse model. PTH treatment exacerbated right ventricular hypertrophy and right ventricular systolic pressure in Hx mice. Our data showed how is PTH effected for PH model murine lung.
2023-10-11 | GSE244861 | GEO
Project description:RNA sequencing of lung tissue from wildtype and hypoxia-induced pulmonary hypertension/hypoxia-induced pulmonary hypertension mice under aerobic exercise conditions
| PRJNA1135226 | ENA
Project description:SRY-Box Transcription Factor 17 (SOX17) enhancers variants and mutations are found in patients with pulmonary arterial hypertension (PAH). In human PAH pulmonary microvascular endothelial cells (HPMVEC), there is a significant downregulation of SOX17 expression. We hypothesized that SOX17 deficiency contributes to the pathogenesis of PAH and found that mice with endothelial specific disruption (ecKO Sox17) developed spontaneous pulmonary hypertension (PH) and exacerbated hypoxia-induced PH. Loss of SOX17 in lung ECs induces cell cycle programming, proliferative and anti-apoptotic phenotypes, a process mediated by the activation of E2F Transcription Factor 1 (E2F1) signaling. Pharmacological inhibition of E2F1 in ecKO Sox17 mice attenuated PH and cell cycle programming. Our study demonstrated that endothelial SOX17 deficiency induces PH and targeting E2F1 signaling represents a promising approach in PAH patients.
2023-03-15 | GSE192649 | GEO
Project description:The precise origin of newly formed alpha smooth muscle actin-positive (ACTA2+) cells appearing in non-muscularized vessels in the context of pulmonary hypertension (PH) is still debatable, although it is believed that they predominantly derive from pre-existing vascular smooth muscle cells (VSMCs). Here, Gli1Cre-ERT2; tdTomatoflox mice were used to lineage-trace GLI1+ cells in the context of PH using two independent models of vascular remodeling (VR) and reverse remodeling (RR): Hypoxia and cigarette-smoke exposure (SE). Hemodynamic measurements, right ventricular hypertrophy assessment, flow cytometry, and histological analysis of thick lung sections followed by state-of-the-art 3D reconstruction and quantification using Imaris software were used to investigate the contribution of GLI1+ cells to neo-muscularization of the pulmonary vasculature. The data show that GLI1+ cells are abundant around distal, nonmuscularized vessels during steady state, and that this lineage contributes to around 50% of newly formed ACTA2+ cell around these normally non-muscularized vessels. During RR, cells derived from the GLI1+ lineage are largely cleared in parallel to the reversal of muscularization. Partial ablation of GLI1+ cells greatly prevented VR in response to hypoxia and attenuated the increase in RVSP and right heart hypertrophy. Single-cell RNA sequencing (scRNA-seq) on sorted lineage-labeled GLI1+ cells revealed an Acta2high fraction of cells with pathways in cancer and MAPK signaling as potential players in reprogramming these cells during VR. Analysis of human lungderived material suggests that GLI1 signaling is overactivated in both Group 1 and Group 3 PH and can promote proliferation and myogenic differentiation. Our data highlight GLI1+ cells as an alternative cellular source of VSMCs in PH and suggest that these cells and the associated signaling pathways represent an important therapeutic target for further studies.
2024-05-14 | GSE253415 | GEO
Project description:SRY-Box Transcription Factor 17 (SOX17) enhancers variants and mutations are found in patients with pulmonary arterial hypertension (PAH). In human PAH pulmonary endothelial cells, there is a significant downregulation of SOX17 expression. We hypothesized that SOX17 deficiency contributes to the pathogenesis of PAH and found that mice with endothelial specific disruption (ecKO Sox17) developed spontaneous pulmonary hypertension (PH) and exacerbated hypoxia-induced PH. Loss of SOX17 in lung ECs induced endothelial dysfunctions including upregulation of cell cycle programming and paracrine effect, proliferative and anti-apoptotic phenotypes, impaired cellular junction and BMP signaling. E2F Transcription Factor 1 (E2F1) signaling was showed to mediate the SOX17 deficiency-induced EC dysfunction. Pharmacological inhibition of E2F1 in ecKO Sox17 mice attenuated PH and cell cycle programming. Our study demonstrated that endothelial SOX17 deficiency induces PH through E2F1 and targeting E2F1 signaling represents a promising approach in PAH patients.
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