ScRNA-seq analysis of the livers from the mice treated with a pan-integrin αV inhibitor after pIVCL
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE305630 | GEO | 2026/03/01
REPOSITORIES: GEO
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Project description:We performed scRNA-seq analysis on murin livers after partial inferior vena cava ligation (pIVCL), a mouse model of congestive hepatopathy. We identified connective tissue growth factor (CTGF) as one of the most upregulated genes in pericentral (zones 2 and 3) LSECs. The scRNA-seq analysis also showed that the integrin signaling pathway was activated and the expression of YAP/TAZ target genes was upregulated in pericentral LSECs.
2026-03-01 | GSE291326 | GEO
Project description:We performed scRNA-seq analysis on the livers from the endothelial cell-specific CTGF knockout (KO) mouse or control wild-type (WT) littermate after partial inferior vena cava ligation (pIVCL), a mouse model of congestive hepatopathy. The scRNA-seq analysis showed that CTGF knockout in LSECs suppressed the expression of YAP/TAZ target genes and basement membrane-related genes in LSECs caused by hepatic congestion.
2026-03-01 | GSE305482 | GEO
Project description:We created a rat renal congestion model and investigated the effect of renal congestion on hemodynamics and molecular mechanisms. The inferior vena cava (IVC) between the renal veins was ligated by suture in male Sprague-Dawley rats to increase upstream IVC pressure and induce congestion in the left kidney only. Left kidney congestion reduced renal blood flow, glomerular filtration rate, and increased renal interstitial hydrostatic pressure. Tubulointerstitial and glomerular injury and medullary thick ascending limb hypoxia were observed only in the congestive kidneys. Molecules related to extracellular matrix expansion, tubular injury, and focal adhesion were upregulated in microarray analysis. Renal decapsulation ameliorated the tubulointerstitial injury. Electron microscopy captured pericyte detachment in the congestive kidneys. Transgelin and platelet-derived growth factor receptors, as indicators of pericyte-myofibroblast transition, were upregulated in the pericytes and the adjacent interstitium. With the compression of the peritubular capillaries and tubules, hypoxia and physical stress induce pericyte detachment, which could result in extracellular matrix expansion and tubular injury in renal congestion.
2018-11-14 | GSE114031 | GEO
Project description:Background & Aims Congestion alters the microenvironment of the liver sinusoid along the portal-central axis. We studied spatial changes in immune cells in the sinusoid which contribute to congestive fibrosis and portal hypertension (PHTN). Methods To visualize the distribution of immune cells in congestive hepatopathy (CH), we performed imaging mass cytometry (IMC) on liver tissue from patients with CH, Fontan-associated liver disease (FALD), and controls. We performed partial ligation of the inferior vena cava (pIVCL) to simulate CH in mice and isolated primary liver cells for single cell RNA-sequencing (scRNA-seq) to study zonation of liver sinusoidal endothelial cells (LSECs). After pIVCL, mice were treated with intraperitoneal injections of AMG487, an inhibitor of the CXCL9 receptor. Results Peri-central macrophages are enriched in CH and FALD. Given the role of CXCL9 in macrophage patterning in the liver, we performed RNA in situ hybridization (RNAish) in CH and determined that CXCL9 was highly expressed in LSECs in FALD, suggesting that LSECs recruit macrophages in CH. After pIVCL, treatment with AMG487 attenuated portal pressures, fibrosis, and intra-hepatic macrophages. To study changes in LSECs which promote macrophage chemotaxis, we performed scRNA-seq after pIVCL and sham procedures. Analysis revealed 3 LSEC subpopulations according to sinusoidal location. RNANish identified peri-central LSECs as the predominant source of CXCL9 in FALD. In vitro analyses revealed that -catenin and hypoxia inducible factor-1α regulate CXCL9 transcription in peri-central LSECs. Conclusions CXCL9 derived from peri-central LSECs enriches intra-hepatic macrophages in CH and FALD, contributing to congestive fibrosis and PHTN. Strategies to target LSEC-derived CXCL9 may prevent the progression of CH and FALD.
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Project description:Thoracic aortic aneurysm (TAA) is a perilous disease that can lead to aortic dissection (AD), the pathophysiological mechanisms of which remain largely elusive. To improve our understanding of the molecular mechanism underlying TAA, we conducted a tandem mass tag (TMT)-based proteomics analysis and identified two down-regulated proteins, integrin αV, and integrin αL, in serum samples from patients with type A aortic dissection. We confirmed that integrin αV is extensively expressed in the aortic media, and its expression decreases after dissection, whereas the expression of integrin αL showed no significant alteration. Subsequently, by employing a mouse model of TAA induced by β-Aminopropionitrile (BAPN), we discovered that the mice treated with integrin αV inhibitors Cilengitide or SB273005 developed dramatically expansive ascending TAA, accompanied by exacerbated disorganization or loss of elastic fibers. Bulk RNA sequencing results further indicated that the treatment with integrin αV inhibitors exacerbates the pro-inflammatory response in mouse TAA development. These data suggest that integrin αV may be a novel target for TAA intervention. However, it also raises concerns about exposure to integrin αV inhibitors, which are conducted in serious cancer clinical trials, may pose a potential risk of developing aortic aneurysm (AA)/AD.
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Project description:Thoracic aortic aneurysm (TAA) is a perilous disease that can lead to aortic dissection (AD), the pathophysiological mechanisms of which remain largely elusive. To improve our understanding of the molecular mechanism underlying TAA, we conducted a tandem mass tag (TMT)-based proteomics analysis and identified two down-regulated proteins, integrin αV, and integrin αL, in serum samples from patients with type A aortic dissection. We confirmed that integrin αV is extensively expressed in the aortic media, and its expression decreases after dissection, whereas the expression of integrin αL showed no significant alteration. Subsequently, by employing a mouse model of TAA induced by β-Aminopropionitrile (BAPN), we discovered that the mice treated with integrin αV inhibitors Cilengitide or SB273005 developed dramatically expansive ascending TAA, accompanied by exacerbated disorganization or loss of elastic fibers. Bulk RNA sequencing results further indicated that the treatment with integrin αV inhibitors exacerbates the pro-inflammatory response in mouse TAA development. These data suggest that integrin αV may be a novel target for TAA intervention. However, it also raises concerns about exposure to integrin αV inhibitors, which are conducted in serious cancer clinical trials, may pose a potential risk of developing aortic aneurysm (AA)/AD.
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Project description:Integrin α5β1 and αv crosstalk in chemotaxis and clonogenic survival of prostate cancer cells is abrogated by a bispecific α5β1/αv antibody (BsAbα5β1/αv), which uniquely induces internalization and lysosomal degradation of target integrins. We hypothesized that the BsAbα5β1/αv inactivates pathological mechanosignaling pathways that correlate with integrin expression from patient samples. Mechanistic studies indicate that the BsAbα5β1/αv uniquely reverses YAP, beta-catenin and FAK nuclear localization compared to monospecific integrin α5β1 and αv antibody controls in basal-type androgen-receptor negative prostate cancer cells. Dual integrin αv and α5 knockdown alone phenocopied the BsAbα5β1/αv effect. Following BsAbα5β1/αv treatment, ATAC-seq studies indicated the chromatin accessibility to TEAD and AP-1 family members was markedly reduced. In vitro and in vivo RNA-seq indicated down-regulation of Myc/E2F, TGF-beta and epithelial mesenchymal transition (EMT) and upregulation of Type I and II interferon transcriptomic pathways. The BsAbα5β1/αv induced CXCL10 and CCL5 cytokine secretion, immune-infiltration of tumors, and natural-killer cell-mediated elimination of the basal-type prostate cancer xenografts in nude mice. αv integrin was highly expressed and principally correlated with the Myc signaling pathway in rapid autopsy tissue microarrays, consistent with correlative data from the SU2C metastatic castration-resistant prostate cancer and DKFZ early-onset prostate cancer cohorts. These studies connect integrin signaling with the central biology of basal-type and castration-resistant prostate cancer and define a novel therapeutic strategy that controls critical immunosuppressive pathways.
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Project description:The number of heart failure (HF) patients is increasing. HF is frequently accompanied by kidney dysfunction and such organ failure is closely related. Recent investigations revealed that increased renal venous pressure, rather than decreased cardiac output, causes the deterioration of kidney function in HF patients; however, the underlying responsible mechanisms are unknown. We demonstrated that reduced blood flow speed in peritubular capillaries (PTCs) by renal congestion and upregulation of nuclear factor-κB (NF-κB) signaling synergistically exacerbate kidney injury. We generated a novel mouse model with unilateral renal congestion by coarctation of the inferior vena cava between renal veins. Intravital imaging highlighted the notable dilatation of PTCs and decreased renal blood flow speed in the congestive kidney. Renal damage after ischemia reperfusion injury was exacerbated in the congestive kidney and accumulation of polymorphonuclear leukocytes (PMNs) within PTCs was observed at the acute phase after injury. Pharmacological inhibition of NF-κB ameliorated renal congestion-mediated exacerbation of kidney injury. In vitro, adhesion of PMNs on the TNFα-stimulated endothelial cells was accelerated by perfusion of PMNs at a slower speed, which was cancelled by the inhibition of NF-κB signaling. Our study demonstrates the importance of slower blood flow accompanying activated NF-κB signaling in the congestive kidney in the exacerbation of renal injury. These mechanisms may explain how increased renal venous pressure in HF patients causes the deterioration of kidney dysfunction. Inhibition of NF-κB signaling may be a therapeutic candidate for the vicious cycle between heart and kidney failure with increased renal venous pressure.
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