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Regulation of NFAT5/TonEBP-mediated transcriptional responses of cholesterol-exposed vascuar smooth muscle cells

ABSTRACT: Objective: To study the impact of NFAT5 overexpression on the transcriptome of cholesterol-exposed murine aortic smooth muscle cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE171637 | GEO | 2021/07/20

REPOSITORIES: GEO

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Genetic ablation of NFAT5/TonEBP in smooth muscle cells impairs flow- and pressure-induced arterial remodeling in mice

Project description:To study the impact of the transcription factor NFAT5 on the vascular smooth muscle cell (VSMC) transcriptome, genetic ablation of floxed nfat5 in mouse aortic smooth muscle cells was achieved by transducing them with an adenoviral vector to express Cre-recombinase (Ad-Cre) under control of a CMV promoter. Empty vector adenovirus (Ad-PL) was used as control.

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Regulation of NFAT5/TonEBP-mediated transcriptional responses of cholesterol-exposed vascuar smooth muscle cells

Project description:Regulation of NFAT5/TonEBP-mediated transcriptional responses of cholesterol-exposed vascuar smooth muscle cells

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Genetic ablation of TonEBP/NFAT5 in smooth muscle cells inhibits arterial remodeling

Project description:Chronic biomechanical stress elicits remodeling of the arterial wall and causes detrimental arterial stenosis and stiffening. In this context, molecular determinants controlling proliferation and stress responses of vascular smooth muscle cells (VSMCs) have been insufficiently studied. We identified the transcription factor ‘nuclear factor of activated T-cells 5’ (NFAT5) as crucial regulatory element of mechanical stress responses of VSMCs. The relevance of this observation for biomechanically induced arterial remodeling was investigated in mice upon SMC-specific knockdown of NFAT5. While blood pressure levels, vascular architecture and flow-induced collateral growth were not affected in these mice, both hypertension-mediated arterial thickening and muscularization of pulmonary arteries during pulmonary artery hypertension (PAH) were impaired. In all models, a decrease in VSMC proliferation was observed indicating that NFAT5 controls activation of VSMCs in the remodeling arterial wall. Mechanistically, mechanoactivation of VSMCs promotes nuclear translocation NFTA5c upon its phosphorylation at Y143 and dephosphorylation at S1197. As evidenced by transcriptome studies, loss of NFAT5 in mechanoactivated VSMCs impairs expression of gene products controlling cell cycle and transcription/translation. These findings identify NFAT5 as molecular determinant of VSMC responses to biomechanical stress and arterial thickening.

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NFAT5/TonEBP controls metabolic adaption and tone of pulmonary vascular smooth muscle cells in the hypoxic lung [SMC]

Project description:Hypoxia provokes adaptive responses of cells, which ensure their energy supply including the adjustment of the transcriptome to match their metabolism. In this context, we explored the transcriptional impact of nuclear factor of activated T-cells 5 (NFAT5) on the function of vascular smooth muscle cells (VSMC) in the hypoxic lung. Exposure to hypoxia induced a rapid nuclear translocation of NFAT5 in cultured murine VSMCs. SMC-specific ablation of Nfat5 (Nfat5(SMC-/-)) increases the systolic pressure in the right ventricle (RVSP) of the mouse heart and impairs its function upon exposure to hypoxia for 7 and 21 days. Analyses of the transcriptome of the lung revealed a robust increase in the expression genes attributed to mitochondrial respiration. Further analyses of hypoxia-exposed pulmonary artery VSMCs revealed that loss of Nfat5 stimulates the expression of multiple mitochondria-related genes encoding cytochrome oxidases while decreasing the expression of lactate dehydrogenase A (Ldha) and phosphofructokinase 3 (Pfkfb3). Both, inhibition of LDHA or PFKFB3 activity and loss of Nfat5 stimulated the mitochondrial production of reactive oxygen species (ROS) in hypoxic pulmonary artery VSMCs while scavenging of ROS normalized the RVSP values in hypoxia-exposed Nfat5(SMC-/-) mice. In summary, our findings suggest a crucial role for NFAT5 in adjusting the transcriptome of hypoxia-exposed pulmonary artery VSMCs to support an adequate glycolysis-centered metabolism. Loss of Nfat5 impairs this response thereby fueling the mitochondrial respiration and ROS production that amplifies the hypoxia-mediated constriction of pulmonary arteries.

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Molecular mechanisms vascular smooth muscle cell (VSMC) acquisition of macrophage features in response to cholesterol loading

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Genetic ablation of TonEBP/NFAT5 in smooth muscle cells inhibits arterial remodeling

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