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Interleukin-11 signaling drives vascular smooth muscle phenotypic switching and contributes to aortic remodelling

ABSTRACT: Interleukin-11 signaling drives vascular smooth muscle phenotypic switching and contributes to aortic remodelling

PROVIDER: PRJNA596994 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10745700_1.fastq.gz	Fastqsanger.gz
	SRR10745700_2.fastq.gz	Fastqsanger.gz
	SRR10745701_1.fastq.gz	Fastqsanger.gz
	SRR10745701_2.fastq.gz	Fastqsanger.gz
	SRR10745702_1.fastq.gz	Fastqsanger.gz

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Interleukin-11 signaling drives vascular smooth muscle phenotypic switching and contributes to aortic remodelling

Project description:RNA sequencing of primary human aortic or arterial VSMCs after stimulation with transforming growth factor beta-1 (TGFβ1) revealed marked IL11 upregulation. In vitro, IL11 stimulation of VSMCs resulted in phenotypic switching by increased ECM production and migration/invasion. Neutralizing IL11 antibody treatment abolished phenotypic switching in VSMCs. IL11 plays an important and non-redundant role in VSMC phenotypic switching.

2020-10-20 | GSE142417 | GEO

KLF4-PFKFB3-driven glycolysis is essential for phenotypic switching of vascular smooth muscle cells

Project description:Vascular smooth muscle cells (VSMCs) within atherosclerotic lesions undergo a phenotypic switching in a KLF4-dependent manner. Glycolysis plays important roles in transdifferentiation of somatic cells, however, it is unclear whether and how KLF4 mediates the link between glycolytic switch and VSMCs phenotypic transitions. Here, we show that KLF4 upregulation accompanies VSMCs phenotypic switching in atherosclerotic lesions. KLF4 enhances the metabolic switch to glycolysis through increasing PFKFB3 expression. Inhibiting glycolysis suppresses KLF4-induced VSMCs phenotypic switching, demonstrating that glycolytic shift is required for VSMCs phenotypic switching. Mechanistically, KLF4 upregulates expression of circCTDP1 and eEF1A2, both of which cooperatively promote PFKFB3 expression. TMAO induces glycolytic shift and VSMCs phenotypic switching by upregulating KLF4. Our study indicates that KLF4 mediates the link between glycolytic switch and VSMCs phenotypic transitions, suggesting that a previously unrecognized KLF4-eEF1A2/circCTDP1-PFKFB3 axis plays crucial roles in VSMCs phenotypic switching.

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Interleukin-11 is important for vascular smooth muscle phenotypic switching and aortic inflammation, fibrosis and remodeling in mouse models.

Project description:Transforming growth factor beta-1 (TGFβ1) is a major driver of vascular smooth muscle cell (VSMC) phenotypic switching, an important pathobiology in arterial disease. We performed RNA-sequencing of TGFβ1-stimulated human aortic or arterial VSMCs which revealed large and consistent upregulation of Interleukin 11 (IL11). IL11 has an unknown function in VSMCs, which highly express the IL11 receptor alpha, suggestive of an autocrine loop. In vitro, IL11 activated ERK signaling, but inhibited STAT3 activity, and caused VSMC phenotypic switching to a similar extent as TGFβ1 or angiotensin II (ANGII) stimulation. Genetic or therapeutic inhibition of IL11 signaling reduced TGFβ1- or ANGII-induced VSMC phenotypic switching, placing IL11 activity downstream of these factors. Aortas of mice with Myh11-driven IL11 expression were remodeled and had reduced contractile but increased matrix and inflammatory genes expression. In two models of arterial pressure loading, IL11 was upregulated in the aorta and neutralizing IL11 antibodies reduced remodeling along with matrix and pro-inflammatory gene expression. These data show that IL11 plays an important role in VSMC phenotype switching, vascular inflammation and aortic pathobiology.

| S-EPMC7576123 | biostudies-literature

KLF4-PFKFB3-driven glycolysis is essential for phenotypic switching of vascular smooth muscle cells (mRNA microarray)

2022-12-14 | GSE216303 | GEO

KLF4-PFKFB3-driven glycolysis is essential for phenotypic switching of vascular smooth muscle cells (circRNA microarray)

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Excessive adventitial stress drives inflammation-mediated fibrosis in hypertensive aortic remodelling in mice

Project description:Hypertension induces significant aortic remodelling, often adaptive but sometimes not. To identify immuno-mechanical mechanisms responsible for differential remodelling, we studied thoracic aortas from 129S6/SvEvTac and C57BL/6 J mice before and after continuous 14-day angiotensin II infusion, which elevated blood pressure similarly in both strains. Histological and biomechanical assessments of excised vessels were similar at baseline, suggesting a common homeostatic set-point for mean wall stress. Histology further revealed near mechano-adaptive remodelling of the hypertensive 129S6/SvEvTac aortas, but a grossly maladaptive remodelling of C57BL/6 J aortas. Bulk RNA sequencing suggested that increased smooth muscle contractile processes promoted mechano-adaptation of 129S6/SvEvTac aortas while immune processes prevented adaptation of C57BL/6 J aortas. Functional studies confirmed an increased vasoconstrictive capacity of the former while immunohistochemistry demonstrated marked increases in inflammatory cells in the latter. We then used multiple computational biomechanical models to test the hypothesis that excessive adventitial wall stress correlates with inflammatory cell infiltration. These models consistently predicted that increased vasoconstriction against an increased pressure coupled with modest deposition of new matrix thickens the wall appropriately, restoring wall stress towards homeostatic consistent with adaptive remodelling. By contrast, insufficient vasoconstriction permits high wall stresses and exuberant inflammation-driven matrix deposition, especially in the adventitia, reflecting compromised homeostasis and gross maladaptation.

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Project description:Apatinib (YN968D1) is a small-molecule tyrosine kinase inhibitor（TKI）which can inhibit the activity of vascular endothelial growth factor receptor-2 (VEGFR-2). It has been reported that apatinib has anti-tumour effect of inhibiting proliferation and inducing apoptosis of a variety of solid tumour cells, whereas its effect on vascular smooth muscle cells (VSMC) remains unclear. This study investigated the effect of apatinib on phenotypic switching of arterial smooth muscle cells in vascular remodelling. Compared to the vehicle groups, mice that were performed carotid artery ligation injury and treated with apatinib produced a reduction in abnormal neointimal area. For in vitro experiment, apatinib administration inhibited VSMC proliferation, migration and reversed VSMC dedifferentiation with the stimulation of platelet-derived growth factor type BB (PDGF-BB).In terms of mechanism, with the preincubation of apatinib, the activations of PDGF receptor-β (PDGFR-β) and phosphoinositide-specific phospholipase C-γ1 (PLC-γ1) induced by PDGF-BB were inhibited in VSMCs. With the preincubation of apatinib, the phosphorylation of PDGFR-β, extracellular signal-related kinases (ERK1/2) and Jun amino-terminal kinases (JNK) induced by PDGF-BB were also inhibited in rat vascular smooth muscle cell line A7r5. Herein, we found that apatinib attenuates phenotypic switching of arterial smooth muscle cells induced by PDGF-BB in vitro and vascular remodelling in vivo. Therefore, apatinib is a potential candidate to treat vascular proliferative diseases.

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Transcription profiling of human aortic smooth muscle cells exposed to hypoxia

Project description:Systemic arterial smooth muscle cells are exposed to a broad range of oxygen concentrations under physiological conditions. Hypoxia can modulate the proliferative response of smooth muscle cells leading to speculation about its role in vasculogenesis, vascular remodelling and the pathogenesis of arterial disease. The effect of hypoxia has been inconsistent, however, with both enhanced proliferation and growth arrest reported. Nevertheless, these reports support an important effect of hypoxia on smooth muscle cell proliferation and, given its physiological and clinical relevance, this requires clarification. We posited that variation in O2 concentration, within the range that exists in vivo, may have different effects on the proliferation and survival of vascular smooth muscle cells. Experiment Overall Design: Human aortic smooth muscle cells (HASMC) were propagated to passage 6 in SMGM-2 medium reached 80% confluence, the media was changed and the cells were incubated for a further 16 hrs or 48 hrs under either normoxic or hypoxic conditions (1% and 3%O2 ).

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Excessive adventitial stress drives inflammation-mediated fibrosis in hypertensive aortic remodelling in mice

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