FXR1 regulates vascular smooth muscle cell cytoskeleton, VSMC contractility, and blood pressure by multiple mechanisms

• Published in: Cell reports (Cambridge) Vol. 42; no. 4; p. 112381
• Main Authors: St. Paul, Amanda, Corbett, Cali, Peluzzo, Amanda, Kelemen, Sheri, Okune, Rachael, Haines, Dale S., Preston, Kyle, Eguchi, Satoru, Autieri, Michael V.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.04.2023; Elsevier
• Subjects: Actins - metabolism; Animals; Blood Pressure; Cells, Cultured; CP: Cell biology; cytoskeletal; Cytoskeletal Proteins - metabolism; Cytoskeleton - metabolism; Humans; Mice; mRNA stability; Muscle Proteins - metabolism; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - metabolism; RNA-Binding Proteins - metabolism; vascular smooth muscle cell; WRC proteins; cytoskeletal; blood pressure; vascular smooth muscle cell; CP: Cell biology; WRC proteins; mRNA stability
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112381

Appropriate cytoskeletal organization is essential for vascular smooth muscle cell (VSMC) conditions such as hypertension. This study identifies FXR1 as a key protein linking cytoskeletal dynamics with mRNA stability. RNA immunoprecipitation sequencing (RIP-seq) in human VSMCs identifies that FXR1 binds to mRNA associated with cytoskeletal dynamics, and FXR1 depletion decreases their mRNA stability. FXR1 binds and regulates actin polymerization. Mass spectrometry identifies that FXR1 interacts with cytoskeletal proteins, particularly Arp2, a protein crucial for VSMC contraction, and CYFIP1, a WASP family verprolin-homologous protein (WAVE) regulatory complex (WRC) protein that links mRNA processing with actin polymerization. Depletion of FXR1 decreases the cytoskeletal processes of adhesion, migration, contraction, and GTPase activation. Using telemetry, conditional FXR1SMC/SMC mice have decreased blood pressure and an abundance of cytoskeletal-associated transcripts. This indicates that FXR1 is a muscle-enhanced WRC modulatory protein that regulates VSMC cytoskeletal dynamics by regulation of cytoskeletal mRNA stability and actin polymerization and cytoskeletal protein-protein interactions, which can regulate blood pressure. [Display omitted] •FXR1 interacts with cytoskeletal RNAs to regulate their abundance and stability•FXR1 interacts with cytoskeletal proteins, such as WAVE proteins CYFIP1 and ARP2•FXR1 regulates cytoskeletal-dependent processes in vascular smooth muscle cells•The genetic deletion of FXR1 in smooth muscle decreases blood pressure in mice St. Paul et al. show that FXR1 links mRNA processing with actin dynamics in vascular smooth muscle cells by binding to mRNAs and proteins that regulate the cytoskeleton. Deletion of FXR1 leads to decreased cellular migration, adhesion, and contraction. Additionally, mice without FXR1 have decreased blood pressure.