FXR1 regulates vascular smooth muscle cell cytoskeleton, VSMC contractility, and blood pressure by multiple mechanisms
Amanda St. Paul,
Cali Corbett,
Amanda Peluzzo,
Sheri Kelemen,
Rachael Okune,
Dale S. Haines,
Kyle Preston,
Satoru Eguchi,
Michael V. Autieri
Affiliations
Amanda St. Paul
Lemole Center for Integrated Lymphatics Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
Cali Corbett
Lemole Center for Integrated Lymphatics Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
Amanda Peluzzo
Lemole Center for Integrated Lymphatics Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
Sheri Kelemen
Lemole Center for Integrated Lymphatics Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
Rachael Okune
Lemole Center for Integrated Lymphatics Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
Dale S. Haines
Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
Kyle Preston
Lemole Center for Integrated Lymphatics Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
Satoru Eguchi
Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA
Michael V. Autieri
Lemole Center for Integrated Lymphatics Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA; Corresponding author
Summary: 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.
