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RGS5 channels intracellular signaling pathways to feature growth arrest of vascular smooth muscle cells

ABSTRACT: Members of the regulator of G-protein signaling (RGS) family terminate the activity of specific Ga subunits. As such, RGS5 acts as an inhibitor of Gαq/11 and Gαi/o activity in vascular smooth muscle cells (VSMCs), which regulate the arterial tone and blood pressure. While Rgs5 shows a variable expression in different types of mouse arteries, neither global nor SMC-specific genetic ablation of Rgs5 altered the blood pressure. To study the impact of RGS5 on the VSMC phenotype and signaling, Rgs5 expression was silenced by siRNA in 3D spheroids supporting a contractile VSMC phenotype. Loss of RGS5 elevated the baseline calcium level and the agonist-induced Gαq/11-mediated release of calcium but inhibited RhoA activity. In contrast, overexpression of RGS5 in 2D-cultured proliferating VSMCs promotes their resting state as evidenced by gene expression array-based analyses and attenuated the activity of Akt- and MAP kinase-related signaling cascades. Moreover, RGS5 overexpression attenuated ERK1/2 phosphorylation, VSMC proliferation and migration, which was mimicked by selectively inhibiting Gαi/o but not Gαq/11 activity. Collectively, the heterogeneous expression level of Rgs5 suggests artery type-specific functions comprising the inhibition of acute agonist-induced Gαq/11/calcium-mediated VSMC contraction as well as the support of a resting VSMC phenotype with low ERK1/2 activity by chronically suppressing the activity of Gαi/o.

ORGANISM(S): Homo sapiens

PROVIDER: GSE174130 | GEO | 2021/07/19

REPOSITORIES: GEO

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Project description:Vascular smooth muscle cell (VSMC) dysregulation is a hallmark of vascular disease, including atherosclerosis. In particular, the majority of cells within atherosclerotic lesions are generated from pre-existing VSMCs and a clonal nature has been documented for VSMC-derived cells in multiple disease models. However, the mechanisms underlying the generation of oligoclonal lesions and the phenotype of proliferating VSMCs are unknown.Here we analyse clonal dynamics in multi-color lineage-traced animals over time after vessel injury to understand the cellular mechanisms underlying clonal VSMC expansion in disease.We demonstrate that VSMC proliferation is initiated in a small fraction of VSMCs that initially expand clonally in the medial layer and then migrate to form the oligoclonal neointima. Selective activation of VSMC proliferation also occurs in vitro, suggesting that this is a cell-autonomous feature. Mapping of VSMC trajectories using single-cell RNA-sequencing reveals a continuum of cellular states after injury and suggests that VSMC proliferation initiates in cells that have downregulated the contractile phenotype and show evidence of pronounced phenotypic switching. We show that proliferation is associated with induced expression of stem cell antigen 1 (SCA1) and the expression signature previously identified in SCA1+ VSMCs in healthy arteries. A remarkably increased proliferation of SCA1+ VSMCs, directly validated in functional assays, indicates that SCA1+ VSMCs act as "first responders" in vascular injury. Early atherosclerotic lesions also had clonal VSMC contribution and we show that the proliferation-associated injury response is conserved in plaque VSMCs, extending these findings to atherosclerosis. Finally, we identify VSMCs in healthy human arteries that correspond to the SCA1+ state in mouse VSMCs and show that genes identified as differentially expressed in this human VSMC subpopulation are enriched for genes showing genetic association with cardiovascular disease. We show that cell-intrinsic, selective VSMC activation drives clonal proliferation after injury and in atherosclerosis. Our study suggests that healthy mouse and human arteries contain VSMCs characterised by expression of disease-associated genes that are predisposed for proliferation. Targeting such "first responder" cells in patients undergoing vascular surgery could effectively prevent injury-associated VSMC activation and neoatherosclerosis.

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RGS5 channels intracellular signaling pathways to feature growth arrest of vascular smooth muscle cells

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