Comaparision of WT and JNK3 KO (MAPK10-/-) gene expression in muscle
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE135853 | GEO | 2019/08/15
REPOSITORIES: GEO
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Project description:Vascular remodeling to match arterial diameter to tissue metabolic requirements commonly fails in ischemic disease. Endothelial cells (EC) sense fluid shear stress (FSS) from blood flow to maintain FSS within a narrow range in healthy vessels. Higher FSS induces vessel outward remodeling to return FSS to physiological levels, but mechanisms are poorly understood. We previously reported that Smad1/5 is maximally activated at physiological FSS and suppressed at higher flow. The Smad1/5 pathway opposes activation of Akt, suggesting that inhibiting Smad1/5 may be required for outward remodeling. Here, we report that suppression of Smad1/5 at high FSS is mediated by elevated KLF2, which induces the BMP pathway inhibitor BMPER, which suppresses Smad1/5 and de-inhibits Akt. In a mouse arteriovenous fistula (AVF) model, high FSS induces arterial outward remodeling coincident with elevated BMPER expression and Smad1/5 inactivation. Endothelial BMPER deletion impaired blood flow recovery and vascular remodeling in the AVF and a hindlimb ischemia (HLI) model, with the latter reversed by BMP9/10 blocking antibodies (bAbs). In both STZ-induced type 1 and HFD-induced type 2 diabetic mice that show poor recovery from HLI, BMP9/10 bAbs improved outcomes. Thus, suppression of Smad1/5 is required for high FSS-mediated outward remodeling and is a potential therapeutic approach for ischemic disease.
2024-05-24 | GSE267813 | GEO
Project description:Background: Endothelial cells (ECs) use glycolysis to produce energy. In pre-clinical models of peripheral arterial disease (PAD), the further activation of EC glycolysis was ineffective and/or deleterious in promoting hypoxia-dependent angiogenesis while pentose phosphate pathway (PPP) activation was effective. Hexosamine biosynthesis pathway (HBP), PPP, and glycolysis are closely linked. Glucosamine directly activates HBP.Methods:Hind-limb ischemia (HLI)ineNOS-/-and Balb/c mice was used. Glucosamine (600 ug/g/day) was injected intraperitoneally. Blood flow recovery was assessed using laser Doppler perfusion imaging (LDPI), angiogenesis was studied by CD31immunostaining.In-vitro: human umbilical vein ECs (HUVECs) and mouse microvascular EC with glucosamine, L-glucose or vascular endothelial growth factor (VEGF165a), were tested underhypoxiaand serum starvation (HSS). Cell counting kit-8 (CCK-8), tube formation, intracellular reactive oxygen species (ROS), Electric Cell-substrate Impedance Sensing (ECIS) and FITC dextran permeability were assessed. Glycolysis and oxidative phosphorylation were assessed by seahorse assay. Gene expression was assessed using RNA sequencing, real-time qPCR, and western blot. Human muscle biopsies from patients with PAD were assessed for EC O-GlcNAcylation before and after supervised exercise vs. standard medical care. Results: Day-3 post-HLI,glucosamine vs. control-treated eNOS-/-had less necrosis.Beginning Day-7 post-HLI, glucosamine vs. control-treated Balb/chad higherblood flowthat persisted to Day-21whereischemic musclesshowed greaterCD31 staining/muscle fiber. In-vitro,glucosamine vs. L-glucoseshowedimproved EC survival and tube formation. RNA-sequencing of glucosamine vs. L-glucose showed increased amino acid metabolism. That resulted in increased oxidative phosphorylation and serine biosynthesis pathway (SBP) without an increase in glycolysis or PPP genes. This was associated with better barrier function and less ROS compared to activating glycolysis by VEGF165a. These effects were mediated by activating transcription factor 4 (ATF4); a driver of exercise-induced angiogenesis. Finally, in muscle biopsies from humans with PAD,EC/O-GlcNAcylation was increased by 12 weeks of supervised exercise vs. standard medical care. Conclusion: In-cells, mice, and humans activation of HBP by glucosamine in PAD inducesan “exercise-like” angiogenesis and offers a promising novel therapeutic pathway to treat this challenging disorder.
2024-06-29 | GSE270552 | GEO
Project description:Background: Lower-limb peripheral artery disease (PAD) is one of the major complications of diabetes mellitus. PAD is associated with poor limb and cardiovascular prognoses, along with a dramatic decrease in life expectancy. Despite major medical advances in the treatment of diabetes, a substantial therapeutic gap remains in the PAD population. Praliciguat is an orally available soluble guanylate cyclase (sGC) stimulator that has been reported both pre-clinically and in early-stage clinical trials to have favorable effects in metabolic and hemodynamic outcomes, suggesting that it may have a potential beneficial effect in PAD. Objective: We evaluated the effect of praliciguat on hind limb ischemia (HLI) recovery in a mouse model of type 2 diabetes. Methods: HLI was induced in leptin receptor-deficient (Leprdb/db) mice by ligation and excision of the left femoral artery. Praliciguat (10 mg/kg/day) was administered in the diet starting 3 days before surgery. Results: 28 days after surgery, ischemic foot perfusion and function parameters were better in praliciguat-treated mice than in vehicle controls. Improved ischemic foot perfusion was not associated with either improved traditional cardiovascular risk factors (i.e., weight, glycemia) or increased angiogenesis. However, treatment with praliciguat significantly increased arteriole diameter, decreased intercellular adhesion molecule 1 (ICAM1) expression, and prevented the accumulation of oxidative pro-angiogenic and pro-inflammatory muscle fibers. While investigating the mechanism underlying the beneficial effects of praliciguat therapy, we found that praliciguat significantly downregulated Myh2 and Cxcl12 mRNA expression in cultured myoblasts and that conditioned medium form praliciguat-treated myoblast decreased ICAM-1 mRNA expression in endothelial cells. These results suggest that praliciguat therapy may decrease ICAM-1 expression in endothelial cells by downregulating Cxcl12 in myocytes. Conclusion: Our results demonstrated that praliciguat promotes blood flow recovery in the ischemic muscle of mice with type 2 diabetes, at least in part by increasing arteriole diameter and by downregulating ICAM-1 expression.
2022-11-11 | GSE217514 | GEO
Project description:We studied metabolic angiocrine mechanisms by which endothelial cell_ECs_ can contribute to muscle regeneration from ischemia by using endothelial specific pfkfb3 knockout mice_pfkfb3DEC_ after hind-limb ischemia_HLI_. During muscle regeneration, monocytes are recruited to the injured area and rapidly become macrophages which initially exhibit a more pro-inflammatory M1-like phenotype but soon thereafter functionally repolarize towards an M2-like phenotype to actively support muscle regeneration. Interestingly, macrophages derived from pfkfb3DEC failed to polarized to M2-like macrophages after HLI. Reduced macrophage polarization impairs angiogenesis and muscle regeneration. The RNAseq data are pfkfb3DEC and pfkfb3WT muscle derived macrophages 3 days after HLI.
2020-05-18 | GSE148584 | GEO
Project description:Regulatory T cells (Tregs) are critically involved in neovascularization, an important compensatory mechanism in peripheral artery disease (PAD). The contribution of G protein coupled receptor 174 (GPR174), which is a regulator of Treg function and development, in neovascularization remains elusive. Here, we reveal that genetic deletion of GPR174 in Tregs potentiated blood flow recovery in mice after hindlimb ischemia (HLI). GPR174 deficiency upregulates amphiregulin (AREG) expression in Tregs, thereby enhancing endothelial cell functions and reducing pro-inflammatory macrophage polarization and endothelial cell apoptosis. Mechanically, GPR174 regulates AREG expression by inhibiting the nuclear accumulation of early growth response protein 1 (EGR1) via Gαs/cAMP/PKA signal pathway activation. Collectively, these findings demonstrate that GPR174 negatively regulates angiogenesis and vascular remodeling in response to ischemic injury and that GPR174 may be a potential molecular target for therapeutic interventions of ischemic vascular diseases.
2022-10-03 | GSE214684 | GEO
Project description:A Microarray Search for Effects of Thyrotropin and Iodide on Angiogenesis Factors Objective: Excess iodide has been administered to hyperthyroid patients before thyroid surgery to reduce intraoperative bleeding and oozing. The purpose of this study was to elucidate the mechanism by which iodide reduces blood flow in the hypervascular thyroid gland. Design: Human thyroid follicles were cultured in the presence or absence of thyrotropin (TSH), or in medium containing various concentrations of iodide, and TSH- or iodide-regulated gene expression was analyzed by cDNA microarray. Main outcome: TSH stimulated the expression of thyroglobulin, peroxidase, sodium-iodide symporter, vascular endothelial growth factor (VEGF)-A, VEGF-B, and placental growth factor (PGF) but decreased that of VEGF-C by half. When thyroid follicles were cultured in high-iodide (10-5M) medium, TSH-induced expression of VEGF-A, VEGF-B and PGF was decreased, accompanied by a reduction of VEGF-A release into the medium. Furthermore, expression of putative angiogenesis inhibitors such as urokinase-type plasminogen activator (PLAU) was increased. These findings were confirmed by real-time polymerase chain reaction (PCR) and Northern blot hybridization. Conclusions: We have demonstrated for the first time that iodide at high concentration decreases the expression of the angiogenic factors VEGF-A, VEGF-B, and PGF, accompanied by an increase in the expression of possible anti-angiogenic factors such as PLAU. These proangiogenic and antiangiogenic factors may at least partly account for the iodide-induced decrease in thyroid blood flow.
2008-08-01 | GSE12244 | GEO
Project description:To validate the findings from scRNA-seq, we purified CD11b+/F480+ macrophages by FACS from the hind limb muscle of C57BL/6 (n=3) and BALB/c (n=2) mice at 3-days post HLI for bulk RNA-seq analysis We then performed gene expression profiling analysis using data obtained from RNA-seq of isolated macrophages from C57BL/6 and BALB/c mice at day 3 after HLI surgery.
2023-10-16 | GSE227076 | GEO
Project description:Purpose: To clarify cellular and molecular mechanisms underlying impaired post-ischemic adaptive vascular responses and to evaluate reconstituted HDL (rHDL)-ApoA-I nanotherapy to rescue the defect in type 2 diabetic (T2DM) mouse model of hindlimb ischemia (HLI). Methods: Mice with beta-cell specific over-expression of insulin-like growth factor-2 in atherosclerotic background (IGF-II/ LDLR-/-ApoB100/100) with T2DM features were used in the study with C57BL/6J mice fed with a regular chow-diet (R36, Lactamin) serving as controls. Mice aged between 16 to 20 weeks were used in the study . Mice were anaesthetized with 1.5-2% isoflurane/air mixture during the surgical procedure. Hair was removed from the operation site and cleaned with sterile water. Single incision was made just above medial thigh and superficial femoral artery was separated from femoral vein and nerve. HLI was induced by unilateral ligation of femoral artery distal to the origin of the profunda femoral artery. The skin was closed with interrupted silk sutures. Mice were were administered with reconstituted ApoA-I nanoparticles with phosphatidyl serine core (rHDL) intravenously starting 2 days post-HLI with doses every 2 days until scarification with Saline injections serving as controls. Adductors muscle aortic endothelial cells (AECs) and Ischemic muscle Macrophages and Endothelial Cells (ECs) were isolated using a combination of magnetic assisted cell sorting and flow Cytometry using Macrophage (F4/80) and EC (CD-31) specific markers. Total RNA isolated from FACS sorted cells were used for RNA seq library preparation. Results: Cell-specific gene expression, flow cytometry and immunohistochemistry revealed a persistent Macrophage and Endothelial cell inflammation and a reduced anti-inflammatory M2-macrophage activation associated with impaired collateral remodelling and sprouting angiogenesis in T2DM mice. Furthermore, reconstituted HDL (rHDL)- ApoA-I was found to rescue impaired collateral remodelling and angiogenesis in T2DM mice through modulating EC and macrophage phenotypes. Conclusions: Our results suggest that an impaired collateral remodelling and sprouting angiogenesis in T2DM mice after HLI is associated with a persistent EC and macrophage inflammation and a reduced activation of anti-inflammatory M2-macrophage. Skewing the macrophage phenotype towards the pro-arteriogenic and pro-angiogenic anti-inflammatory M2-macrophages using reconstituted HDL (rHDL)-ApoA-I nanotherapy may serve as a potential therapeutic modality for T2DM PAD.
2023-01-30 | GSE197392 | GEO
Project description:Background: Increased proliferation of airway smooth muscle (ASM) cells leading to hyperplasia and increased ASM mass is one of the most characteristic features of airway remodelling in asthma. A bioactive lipid, sphingosine-1-phosphate (S1P), has been suggested to affect airway remodelling by stimulation of human ASM cell proliferation. Objective: To investigate the effect of S1P on signalling and regulation of gene expression in ASM cells from healthy and asthmatic individuals. Methods: ASM cells grown from bronchial biopsies of healthy and asthmatic individuals were exposed to S1P. Gene expression was analysed using microarray, real-time PCR and western blotting. Receptor signalling and function was determined by mRNA knockdown and intracellular calcium mobilisation experiments. Results: S1P potently regulated the expression of more than 80 genes in human ASM cells, including several genes known to be involved in the regulation of cell proliferation and airway remodelling (HBEGF, TGFB3, TXNIP, PLAUR, SERPINE1, RGS4). S1P acting through S1P2 and S1P3 receptors activated intracellular calcium mobilisation and extracellular signal-regulated and Rho-associated kinases to regulate gene expression. S1P-induced responses were not inhibited by corticosteroids and did not differ significantly between ASM cells from healthy and asthmatic individuals. Conclusion: S1P induces a steroid-resistant, pro-remodelling pathway in ASM cells. Targeting S1P or its receptors could be a novel treatment strategy for inhibiting airway remodelling in asthma. Airway smooth muscle cells from 3 healthy donors were cultured and stimulated for 4 h with sphingosine-1-phosphate (100 nM) or medium control. Total RNA was extracted and analysed using Affymetrix Human Exon 1.0 ST arrays.
2015-06-18 | E-GEOD-58657 | biostudies-arrayexpress
Project description:Comaparision of WT and JNK3 KO (MAPK10-/-) gene expression in muscle
| PRJNA560286 | ENA