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Role of RhoA and Rho-associated kinase in phenotypic switching of vascular smooth muscle cells: Implications for vascular function

  • Tedy Sawma
    Affiliations
    Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Lebanon
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Abdullah Shaito
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Biomedical Research Center, Qatar University, Doha, Qatar
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Nicolas Najm
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Lebanon
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Munir Sidani
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Lebanon
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  • Alexander Orekhov
    Affiliations
    Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Institute of Human Morphology, Moscow, Russia

    Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Moscow, Russia

    Institute for Atherosclerosis Research, Skolkovo Innovative Center, Moscow, Russia
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  • Ahmed F. El-Yazbi
    Affiliations
    Faculty of Pharmacy, Alamein International University, Alamein, Egypt

    Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
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  • Rabah Iratni
    Affiliations
    Department of Biology, College of Science, United Arab Emirates University, Al-Ain, United Arab Emirates
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  • Ali H. Eid
    Correspondence
    Corresponding author.
    Affiliations
    Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar
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  • Author Footnotes
    1 These authors contributed equally to this work.

      Highlights

      • Phenotypic switch of vascular smooth muscle cells (VSMCs) contributes to vascular disease such as atherosclerosis.
      • Modulation of RhoA/ROCK-mediated VSMC contraction process is an integral part of VSMC phenotype switching.
      • RhoA/ROCK modulates proliferation, dedifferentiation, apoptosis and migration of VSMCs.
      • RhoA/ROCK signaling is a key player in arterial stiffness and atherosclerosis.

      Abstract

      Cardiovascular disease (CVD) continues to be the primary cause of global mortality. Vascular smooth muscle cells (VSMCs) are integral components of vascular structure and function, evident by their vital roles in modulating blood flow and pressure. Such roles exist due to the differentiated contractile phenotype of VSMCs. However, VSMCs may switch to a dedifferentiated, proliferative synthetic phenotype in a phenomenon known as phenotypic switching. This switch involves dramatic changes in VSMC migration, proliferation, gene expression programs, differentiation, cellular stiffness and extracellular matrix (ECM) deposition. In this review, we explore the role of the small GTPase Rho and its effector, Rho-associated kinase (ROCK), in phenotypic switching as well as apoptotic pathways in VSMCs. We critically dissect how RhoA promotes cell migration and proliferation as well as its role in modulating the expression of a battery of VSMC marker proteins. We also discuss how RhoA modulates apoptosis, induces dedifferentiation, increases vascular stiffness, or modifies ECM accumulation. These alterations in VSMC phenotypes contribute to multiple vascular dysfunctions, including hypertension and atherosclerosis. Understanding the molecular underpinnings and the signaling pathways involved in these altered phenotypes may provide novel avenues of drug design and other therapeutic interventions for the management of CVDs.

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