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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.

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

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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.

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