A transcriptomic atlas of drug-induced endothelial dysfunction in human endothelial cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE217898 | GEO | 2022/11/21
REPOSITORIES: GEO
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Project description:Diabetes is a known risk factor for various cardiovascular complications, mediated by endothelial dysfunction. Despite the high prevalence of this metabolic disorder, there is a lack of in vitro models that recapitulate the complexity of genetic and environmental factors associated with diabetic endothelial dysfunction. Here, we utilized human induced pluripotent stem cell (iPSC)-derived endothelial cells (ECs) to develop in vitro models of diabetic endothelial dysfunction. We found that the diabetic phenotype was recapitulated in diabetic patient-derived iPSC-ECs, even in the absence of a diabetogenic environment. Subsequent exposure with culture conditions that mimic the diabetic clinical chemistry induced a diabetic phenotype in healthy iPSC-ECs but did not affect the already dysfunctional diabetic iPSC-ECs. RNA-seq analysis revealed extensive transcriptome-wide differences between cells derived from healthy individuals and diabetic patients. The in vitro disease models were used as a screening platform which identified angiotensin receptor blockers (ARBs) that improved endothelial function in vitro for each patient. In summary, we present in vitro models of diabetic endothelial dysfunction using iPSC technology, taking into account the complexity of genetic and environmental factors in the metabolic disorder. Our study provides novel insights into the pathophysiology of diabetic endothelial dysfunction and highlights the potential of iPSC-based models for drug discovery and personalized medicine.
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Project description:Abundant evidence suggests that women with polycystic ovary syndrome (PCOS) have increased metabolic aberrations and cardiovascular risks and present with signs of endothelial cell (EC) dysfunction. However, whether and how androgen is involved in the pathogenesis of EC dysfunction in PCOS remains unclear. Induced pluripotent stem cells (iPSCs) were established in two PCOS patients and two control participants and further differentiated into ECs via monoculture under chemically defined conditions. Both PCOS patients were phenotype A (present with oligomenorrhea, hyperandrogenism, and polycystic ovarian morphology) and were diagnosed with metabolic syndrome. Single-cell transcriptomic analysis of the iPSC-derived ECs revealed functional differences involving the cell cycle process, vascular endothelial growth factor (VEGF) signaling and apoptosis between the PCOS and control groups. Decreased expression of cell proliferation and cell cycle related genes were noted in the PCOS iPSC-derived ECs. Dihydrotestosterone (DHT) treatment significantly enhanced cell proliferation and angiogenic function in the control iPSC-derived ECs. In contrast, significantly deteriorated cell proliferation accompanied with diminished expression of androgen receptor/cyclin-dependent kinase 1/VEGF signaling pathway was shown in the PCOS iPSC-derived ECs after DHT treatment, alongside with impaired angiogenesis demonstrated by the tube formation and wound healing assay. In conclusion, disease-specific iPSCs were successfully established in phenotype A PCOS patients with metabolic syndrome and served as an effective platform for disease modeling in this specific subgroup. Both intrinsic and androgen-induced cellular proliferation and angiogenesis were significantly impaired in the PCOS iPSC-derived ECs, providing new pathogenic evidence for androgen-mediated EC dysfunction and possibly further cardiovascular consequences.
2023-11-01 | GSE246456 | GEO
Project description:Little is known about the function of induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) generated from diabetics, as this could potentially limit subsequent therapeutic use in this patient population. Here, we demonstrate that iPSC-ECs derived from diet-induced obesity (DIO) mice exhibit evidence of endothelial dysfunction. We also observed that mice receiving intramuscular (IM) injections of DIO iPSC-ECs had significantly decreased reperfusion following hindlimb ischemia compared to mice administered with iPSC-ECs from control mice. Hindlimb sections revealed increased muscle atrophy and presence of inflammatory cells in mice receiving iPSC-ECs from DIO mice. When pravastatin was administered to mice receiving DIO iPSC-ECs, a significant increase in reperfusion was observed, which was blunted by co-administration of L-NAME. This study is the first to provide evidence that iPSC-ECs from pre-diabetic mice exhibit signs of endothelial function, and suggest that pravastatin administration may be needed for diabetic patients receiving autologous iPSC-ECs therapy in the clinic. Four samples were analyzed, two from the healthy (control) group and two from the diet-induced obesity group
2014-01-25 | E-GEOD-54387 | biostudies-arrayexpress
Project description:The coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains to spread worldwide. COVID-19 is characterized by the striking high mortality in elderly; however, its mechanistic insights remain unclear. Systemic thrombosis has been highlighted in the pathogenesis of COVID-19, and lung microangiopathy in association with endothelial cells (ECs) injury has been reported by post-mortem analysis of the lungs. Here, we experimentally investigated the SARS-CoV-2 infection in cultured human ECs, and performed a comparative analysis for post-infection molecular events using early passage and replicative senescent ECs. We found that; 1) SARS-CoV-2 infects ECs but does not replicate and disappears in 72 hours without causing severe cell damage, 2) Senescent ECs are highly susceptible to SARS-CoV-2 infection, 3) SARS-CoV-2 infection alters various genes expression, which could cause EC dysfunctions, 4) More genes expression is affected in senescent ECs by SARS-CoV-2 infection than in early passage ECs, which might causes further exacerbated dysfunction in senescent ECs. These data suggest that sustained EC dysfunctions due to SARS-CoV-2 infection may contribute to the microangiopathy in the lungs, leading to deteriorated inflammation and thrombosis in COVID-19. Our data also suggest a possible causative role of EC senescence in the aggravated disease in elder COVID-19 patients.
2023-05-01 | GSE206677 | GEO
Project description:The heterogeneity of endothelial cells (ECs), lining blood vessels, across tissues remains incompletely inventoried. We constructed an atlas of >32,000 single-EC transcriptomic data from 11 tissues of the model organism Mus musculus. We propose a new classification of EC phenotypes based on transcriptome signatures and inferred putative biological features. We identified top-ranking markers for ECs from each tissue. ECs from different vascular beds (arteries, capillaries, veins, lymphatics) resembled each other across tissues, but only arterial, venous and lymphatic (not capillary) ECs shared markers, illustrating a greater heterogeneity of capillary ECs. We identified high-endothelial-venule and lacteal-like ECs in the intestines, and angiogenic ECs in healthy tissues. Metabolic transcriptomes of ECs differed amongst spleen, lung, liver, brain and testis, while being similar for kidney, heart, muscle and intestines. Within tissues, metabolic gene expression was heterogeneous amongst ECs from different vascular beds, altogether highlighting large EC heterogeneity.
2020-02-13 | E-MTAB-8077 | biostudies-arrayexpress
Project description:Aims: Novel cancer therapies leading to increased survivorship of cancer patients have been negated by a concomitant rise in cancer therapies-related cardiovascular toxicities. Sunitinib, a first line multi receptor tyrosine kinase inhibitor (TKI), has been reported to cause vascular dysfunction although the initiating mechanisms contributing to this side effect remain unknown. Long non-coding RNAs (lncRNAs) are emerging regulators of biological processes in endothelial cells (ECs); however, their roles in cancer therapies-related vascular toxicities remain underexplored. Methods and Results: We performed lncRNA expression profiling to identify potential lncRNAs that are dysregulated in human induced pluripotent stem cells-derived ECs (iPSC-ECs) treated with sunitinib. We show that the lncRNA hyaluronan synthase 2 antisense 1 (HAS2-AS1) is significantly diminished in sunitinib-treated iPSC-ECs. Sunitinib was found to downregulate HAS2-AS1 by an epigenetic mechanism involving hypermethylation. Depletion of HAS2-AS1 recapitulated sunitinib-induced detrimental effects on iPSC-ECs, whereas CRISPR-mediated activation of HAS2-AS1 reversed sunitinib-induced dysfunction. We confirm that HAS2-AS1 stabilizes the expression of its sense gene HAS2 via an RNA/mRNA heteroduplex formation. Knockdown of HAS2-AS1 led to reduced synthesis of hyaluronic acid (HA) and upregulation of ADAMTS5, an enzyme involved in extracellular matrix degradation, resulting in disruption of the endothelial glycocalyx which is critical for ECs. In vivo, sunitinib-treated mice showed reduced coronary flow reserve, accompanied by a reduction in has2os and degradation of the endothelial glycocalyx. Finally, we identify that treatment with high molecular-weight HA can prevent the deleterious effects of sunitinib both in vitro and in vivo by preserving the endothelial glycocalyx. Conclusions: Our findings highlight the importance of lncRNA-mediated regulation of the endothelial glycocalyx as an important determinant of sunitinib-induced vascular toxicity and reveal potential novel therapeutic avenues to attenuate sunitinib-induced vascular dysfunction.
2023-04-30 | GSE216453 | GEO
Project description:Aims: Novel cancer therapies leading to increased survivorship of cancer patients have been negated by a concomitant rise in cancer therapies-related cardiovascular toxicities. Sunitinib, a first line multi receptor tyrosine kinase inhibitor (TKI), has been reported to cause vascular dysfunction although the initiating mechanisms contributing to this side effect remain unknown. Long non-coding RNAs (lncRNAs) are emerging regulators of biological processes in endothelial cells (ECs); however, their roles in cancer therapies-related vascular toxicities remain underexplored. Methods and Results: We performed lncRNA expression profiling to identify potential lncRNAs that are dysregulated in human induced pluripotent stem cells-derived ECs (iPSC-ECs) treated with sunitinib. We show that the lncRNA hyaluronan synthase 2 antisense 1 (HAS2-AS1) is significantly diminished in sunitinib-treated iPSC-ECs. Sunitinib was found to downregulate HAS2-AS1 by an epigenetic mechanism involving hypermethylation. Depletion of HAS2-AS1 recapitulated sunitinib-induced detrimental effects on iPSC-ECs, whereas CRISPR-mediated activation of HAS2-AS1 reversed sunitinib-induced dysfunction. We confirm that HAS2-AS1 stabilizes the expression of its sense gene HAS2 via an RNA/mRNA heteroduplex formation. Knockdown of HAS2-AS1 led to reduced synthesis of hyaluronic acid (HA) and upregulation of ADAMTS5, an enzyme involved in extracellular matrix degradation, resulting in disruption of the endothelial glycocalyx which is critical for ECs. In vivo, sunitinib-treated mice showed reduced coronary flow reserve, accompanied by a reduction in has2os and degradation of the endothelial glycocalyx. Finally, we identify that treatment with high molecular-weight HA can prevent the deleterious effects of sunitinib both in vitro and in vivo by preserving the endothelial glycocalyx. Conclusions: Our findings highlight the importance of lncRNA-mediated regulation of the endothelial glycocalyx as an important determinant of sunitinib-induced vascular toxicity and reveal potential novel therapeutic avenues to attenuate sunitinib-induced vascular dysfunction.
2023-04-30 | GSE216452 | GEO
Project description:Little is known about the function of induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) generated from diabetics, as this could potentially limit subsequent therapeutic use in this patient population. Here, we demonstrate that iPSC-ECs derived from diet-induced obesity (DIO) mice exhibit evidence of endothelial dysfunction. We also observed that mice receiving intramuscular (IM) injections of DIO iPSC-ECs had significantly decreased reperfusion following hindlimb ischemia compared to mice administered with iPSC-ECs from control mice. Hindlimb sections revealed increased muscle atrophy and presence of inflammatory cells in mice receiving iPSC-ECs from DIO mice. When pravastatin was administered to mice receiving DIO iPSC-ECs, a significant increase in reperfusion was observed, which was blunted by co-administration of L-NAME. This study is the first to provide evidence that iPSC-ECs from pre-diabetic mice exhibit signs of endothelial function, and suggest that pravastatin administration may be needed for diabetic patients receiving autologous iPSC-ECs therapy in the clinic.
2014-01-25 | GSE54387 | GEO