Homo sapiens
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PROVIDER: PRJNA297615 | ENA |
REPOSITORIES: ENA
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Project description:NextGen Consortium: iPSC Derived EC as Surrogates Using Pulmonary Hypertension as a Prototype Disease
| PRJNA297614 | ENA
Project description:Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a progressive increase in pulmonary artery pressure caused by pathological pulmonary artery remodeling. Here, we show that endothelial cell (EC) senescence plays a negative role in pulmonary hypertension via juxtacrine interaction with smooth muscle cells (SMCs). By using EC-specific progeroid mice that we recently generated, we discovered that EC progeria deteriorated vascular remodeling in the lungs, and exacerbated pulmonary hypertension in mice exposed to chronic hypoxia. Mechanistically, senescent ECs overexpressed Notch ligands, which resulted in increased Notch signaling and activated proliferation and migration capacities in neighboring SMCs. Pharmacological inhibition of Notch signaling reduced the effects of senescent ECs on SMCs functions in vitro, and improved the worsened pulmonary hypertension in EC-specific progeroid mice in vivo. Our findings show that EC senescence is a critical disease-modifying factor in PAH and that EC-mediated Notch signaling is a pharmacotherapeutic target for the treatment of PAH, particularly in the elderly.
2023-04-30 | GSE228491 | GEO
Project description:Pulmonary arterial hypertension (PAH) is a progressive disease in which pulmonary arterial (PA) endothelial cell (EC) dysfunction is associated with unrepaired DNA damage. BMPR2 is the most common mutant gene in PAH. We report that human PAEC with reduced BMPR2 have persistent DNA damage in room air after hypoxic exposure (reoxygenation), as do mice with EC deletion of Bmpr2 (EC-Bmpr2-/-) and persistent pulmonary hypertension. Similar findings are observed in PAEC with loss of the DNA damage sensor ATM, and in mice with Atm deleted in EC (EC-Atm-/-). Gene expression analysis of EC-Atm-/- and EC-Bmpr2-/- lung EC revealed reduced Foxf1, a transcription factor with relative selectivity for lung EC. Reducing FOXF1 in control PAEC induced DNA damage and impaired angiogenesis whereas transfection of FOXF1 in PAH PAEC repaired DNA damage and restored angiogenesis. Lung EC targeted delivery of Foxf1 to reoxygenated EC-Bmpr2-/- mice repaired DNA damage, induced angiogenesis and reversed pulmonary hypertension.
2023-08-15 | GSE215933 | GEO
Project description:Pulmonary hypertension (PH) is a serious complication of sickle cell disease (SCD) associated with increased mortality. Gene expression profiles of peripheral blood mononuclear cells (PBMC) have been studied in pulmonary arterial hypertension and in SCD. We hypothesized that a PBMC-derived gene signature in SCD patients may be utilized as a PH biomarker. Twenty-seven patients with homozygous SCD underwent transthoracic echocardiography and PBMC isolation. PH was defined as estimated right ventricular systolic pressure (RVSP)>30 mmHg with a peak tricuspid regurgitation velocity (TRV)>2.5m/s. Genome-wide gene expression profiles were correlated against PH severity using RVSP and TRV as surrogates, which yielded 631 potentially dysregulated transcripts. Total RNA was isolated from PBMCs using standard molecular biology protocols without DNA contamination or RNA degradation. Sample processing (e.g., cDNA generation, fragmentation, end labeling, hybridization to Affymetrix GeneChip Human Exon 1.0 ST arrays) was performed per manufacturer’s instructions. A total of 27 African descent American patients with sickle cell disease were included in the microarray analysis.
2012-06-06 | E-GEOD-38528 | biostudies-arrayexpress
Project description:Pulmonary hypertension (PH) is a serious complication of sickle cell disease (SCD) associated with increased mortality. Gene expression profiles of peripheral blood mononuclear cells (PBMC) have been studied in pulmonary arterial hypertension and in SCD. We hypothesized that a PBMC-derived gene signature in SCD patients may be utilized as a PH biomarker. Twenty-seven patients with homozygous SCD underwent transthoracic echocardiography and PBMC isolation. PH was defined as estimated right ventricular systolic pressure (RVSP)>30 mmHg with a peak tricuspid regurgitation velocity (TRV)>2.5m/s. Genome-wide gene expression profiles were correlated against PH severity using RVSP and TRV as surrogates, which yielded 631 potentially dysregulated transcripts.
2012-06-07 | GSE38528 | GEO
Project description:Dysfunction of pulmonary arterial endothelial cells (PAECs) is associated with the development and progression of vascular pathology. However, it remains unknown how pulmonary hypertension (PH) affects cellular composition and transcriptomic profile of pulmonary endothelium. Here, we have undertaken a single-cell, compartment specific approach to characterise alterations in PAECs associated with two different types of PH, i.e., pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with pulmonary fibrosis (PHPF). Our unbiased analysis showed that endothelium of medium / small caliber pulmonary arteries is composed of three subsets of endothelial cells (ECs). The analysis of healthy and PH endothelium revealed that the three populations are persistently represented in remodelled arteries. Additionally, an exploratory analysis of human aorta (AO) and coronary arteries (CA) endothelium revealed that, although similar gene expression patterns were noticeable, PAECs subpopulations proportions differs significantly from pulmonary arteries (PA) endothelium. To address whether EC heterogeneity is a prime feature of human endothelium, we also performed a similar analysis in a murine model of hypoxia, revealing that similar EC populations were evident in this animal model. Comparative analysis of EC subpopulations in healthy and PH EC identified a common genetic deregulation accompanying vascular remodelling. Even though murine EC displayed some similarities with human EC subpopulations, the intense re-programming associated with hypoxia associated vascular remodelling displayed significant differences compared to the human disease. Finally, in depth comparative analysis of PAH and PHPF EC highlighted the development of disease-specific transcriptomic alterations in the three populations. Therefore, characterisation of transcriptomic differences in the endothelial bed of PAH and PHPF patients can facilitate identification of novel, disease-specific therapeutic targets.
2024-07-11 | GSE228643 | GEO
Project description:Pulmonary arterial hypertension (PAH) is a progressive fatal disease that is characterized by pathological pulmonary artery remodeling, in which endothelial cell (EC) dysfunction is critically involved. We herein describe a previously unknown role of endothelial angiocrine in pulmonary hypertension. By searching for genes highly expressed in lung microvascular ECs, we identified inhibin--A (INHBA) as an angiocrine factor produced by pulmonary capillaries. We found that excess production of INHBA by ECs impairs the endothelial function in an autocrine manner by functioning as activin A (ActA). Mechanistically, ActA induces bone morphogenetic protein receptor type 2 (BMPRII) internalization and targeting to lysosomes for degradation, resulting in BMPRII signal deficiency in ECs. When endothelial ActA-BMPRII link is overdriven in mice, hypoxia-induced pulmonary hypertension was exacerbated, whereas conditional knockout of INHBA in ECs prevents the progression of pulmonary hypertension. These data collectively indicate a critical role for the dysregulated endothelial ActA-BMPRII link in the progression of pulmonary hypertension, and thus endothelial INHBA/ActA is an attractive pharmacotherapeutic target for the treatment of PAH.
2020-12-15 | GSE156233 | GEO
Project description:Pulmonary arterial hypertension (PAH) is a progressive fatal disease that is characterized by pathological pulmonary artery remodeling, in which endothelial cell (EC) dysfunction is critically involved. We herein describe a previously unknown role of endothelial angiocrine in pulmonary hypertension. By searching for genes highly expressed in lung microvascular ECs, we identified inhibin--A (INHBA) as an angiocrine factor produced by pulmonary capillaries. We found that excess production of INHBA by ECs impairs the endothelial function in an autocrine manner by functioning as activin A (ActA). Mechanistically, ActA induces bone morphogenetic protein receptor type 2 (BMPRII) internalization and targeting to lysosomes for degradation, resulting in BMPRII signal deficiency in ECs. When endothelial ActA-BMPRII link is overdriven in mice, hypoxia-induced pulmonary hypertension was exacerbated, whereas conditional knockout of INHBA in ECs prevents the progression of pulmonary hypertension. These data collectively indicate a critical role for the dysregulated endothelial ActA-BMPRII link in the progression of pulmonary hypertension, and thus endothelial INHBA/ActA is an attractive pharmacotherapeutic target for the treatment of PAH.
2020-12-15 | GSE156225 | GEO
Project description:NextGen Consortium: The iPSCORE (iPSC Collection for Omic Research) Resource
| PRJNA285374 | ENA