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      Recent advances of mechanosensitive genes in vascular endothelial cells for the formation and treatment of atherosclerosis

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          Abstract

          Atherosclerotic cardiovascular disease and its complications are a high-incidence disease worldwide. Numerous studies have shown that blood flow shear has a huge impact on the function of vascular endothelial cells, and it plays an important role in gene regulation of pro-inflammatory, pro-thrombotic, pro-oxidative stress, and cell permeability. Many important endothelial cell mechanosensitive genes have been discovered, including KLK10, CCN gene family, NRP2, YAP, TAZ, HIF-1α, NF-κB, FOS, JUN, TFEB, KLF2/KLF4, NRF2, and ID1. Some of them have been intensively studied, whereas the relevant regulatory mechanism of other genes remains unclear. Focusing on these mechanosensitive genes will provide new strategies for therapeutic intervention in atherosclerotic vascular disease. Thus, this article reviews the mechanosensitive genes affecting vascular endothelial cells, including classical pathways and some newly screened genes, and summarizes the latest research progress on their roles in the pathogenesis of atherosclerosis to reveal effective therapeutic targets of drugs and provide new insights for anti-atherosclerosis.

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          Role of YAP/TAZ in mechanotransduction.

          Cells perceive their microenvironment not only through soluble signals but also through physical and mechanical cues, such as extracellular matrix (ECM) stiffness or confined adhesiveness. By mechanotransduction systems, cells translate these stimuli into biochemical signals controlling multiple aspects of cell behaviour, including growth, differentiation and cancer malignant progression, but how rigidity mechanosensing is ultimately linked to activity of nuclear transcription factors remains poorly understood. Here we report the identification of the Yorkie-homologues YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif, also known as WWTR1) as nuclear relays of mechanical signals exerted by ECM rigidity and cell shape. This regulation requires Rho GTPase activity and tension of the actomyosin cytoskeleton, but is independent of the Hippo/LATS cascade. Crucially, YAP/TAZ are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry; conversely, expression of activated YAP overrules physical constraints in dictating cell behaviour. These findings identify YAP/TAZ as sensors and mediators of mechanical cues instructed by the cellular microenvironment.
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            Endothelial Cell Dysfunction and the Pathobiology of Atherosclerosis.

            Dysfunction of the endothelial lining of lesion-prone areas of the arterial vasculature is an important contributor to the pathobiology of atherosclerotic cardiovascular disease. Endothelial cell dysfunction, in its broadest sense, encompasses a constellation of various nonadaptive alterations in functional phenotype, which have important implications for the regulation of hemostasis and thrombosis, local vascular tone and redox balance, and the orchestration of acute and chronic inflammatory reactions within the arterial wall. In this review, we trace the evolution of the concept of endothelial cell dysfunction, focusing on recent insights into the cellular and molecular mechanisms that underlie its pivotal roles in atherosclerotic lesion initiation and progression; explore its relationship to classic, as well as more recently defined, clinical risk factors for atherosclerotic cardiovascular disease; consider current approaches to the clinical assessment of endothelial cell dysfunction; and outline some promising new directions for its early detection and treatment.
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              Atherosclerosis

              Atherosclerosis, the formation of fibrofatty lesions in the artery wall, causes much morbidity and mortality worldwide, including most myocardial infarctions and many strokes, as well as disabling peripheral artery disease. Development of atherosclerotic lesions probably requires low-density lipoprotein, a particle that carries cholesterol through the blood. Other risk factors for atherosclerosis and its thrombotic complications include hypertension, cigarette smoking and diabetes mellitus. Increasing evidence also points to a role of the immune system, as emerging risk factors include inflammation and clonal haematopoiesis. Studies of the cell and molecular biology of atherogenesis have provided considerable insight into the mechanisms that link all these risk factors to atheroma development and the clinical manifestations of this disease. An array of diagnostic techniques, both invasive (such as selective coronary arteriography) and noninvasive (such as blood biomarkers, stress testing, CT and nuclear scanning), permit assessment of cardiovascular disease risk and targeting of therapies. An expanding armamentarium of therapies that can modify risk factors and confer clinical benefit is available; however, we face considerable challenge in providing equitable access to these treatments and in maximizing adherence. Yet, the clinical application of the fruits of research has advanced preventive strategies, enhanced clinical outcomes in affected individuals, and improved their quality of life. Rapidly accelerating knowledge and continued research promise to provide further progress in combating this common chronic disease.
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                Author and article information

                Contributors
                Journal
                Genes Dis
                Genes Dis
                Genes & Diseases
                Chongqing Medical University
                2352-4820
                2352-3042
                17 July 2023
                May 2024
                17 July 2023
                : 11
                : 3
                : 101046
                Affiliations
                [a ]Key Laboratory of Biorheological Science and Technology of Ministry of Education, National and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing 400030, China
                [b ]College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China
                [c ]Department of Neurosurgery, Daping Hospital, Army Medical Center of PLA, Army Medical University, Chongqing 400042, China
                Author notes
                []Corresponding author. wanggx@ 123456cqu.edu.cn
                [∗∗ ]Corresponding author. zangguangchao@ 123456cqmu.edu.cn
                [1]

                These authors contributed equally to this work.

                Article
                S2352-3042(23)00327-6 101046
                10.1016/j.gendis.2023.06.016
                10825297
                38292174
                8b765a57-1449-4b81-86dc-35247c7e336b
                © 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 18 February 2022
                : 9 May 2023
                : 6 June 2023
                Categories
                Review Article

                atherosclerosis,blood flow,endothelial cell,mechanosensitive gene,therapeutic target

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