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      Endothelial mechanobiology

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          Abstract

          Lining the luminal surface of the vasculature, endothelial cells (ECs) are in direct contact with and differentially respond to hemodynamic forces depending on their anatomic location. Pulsatile shear stress (PS) is defined by laminar flow and is predominantly located in straight vascular regions, while disturbed or oscillatory shear stress (OS) is localized to branch points and bifurcations. Such flow patterns have become a central focus of vascular diseases, such as atherosclerosis, because the focal distribution of endothelial dysfunction corresponds to regions exposed to OS, whereas endothelial homeostasis is maintained in regions defined by PS. Deciphering the mechanotransduction events that occur in ECs in response to differential flow patterns has required the innovation of multidisciplinary approaches in both in vitro and in vivo systems. The results from these studies have identified a multitude of shear stress-regulated molecular networks in the endothelium that are implicated in health and disease. This review outlines the significance of scientific findings generated in collaboration with Dr. Shu Chien.

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          MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice.

          MicroRNAs (miRs) are small noncoding RNAs that regulate gene expression by binding to target messenger RNAs (mRNAs), leading to translational repression or degradation. Here, we show that the miR-17approximately92 cluster is highly expressed in human endothelial cells and that miR-92a, a component of this cluster, controls the growth of new blood vessels (angiogenesis). Forced overexpression of miR-92a in endothelial cells blocked angiogenesis in vitro and in vivo. In mouse models of limb ischemia and myocardial infarction, systemic administration of an antagomir designed to inhibit miR-92a led to enhanced blood vessel growth and functional recovery of damaged tissue. MiR-92a appears to target mRNAs corresponding to several proangiogenic proteins, including the integrin subunit alpha5. Thus, miR-92a may serve as a valuable therapeutic target in the setting of ischemic disease.
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            Piezo1, a mechanically activated ion channel, is required for vascular development in mice.

            Mechanosensation is perhaps the last sensory modality not understood at the molecular level. Ion channels that sense mechanical force are postulated to play critical roles in a variety of biological processes including sensing touch/pain (somatosensation), sound (hearing), and shear stress (cardiovascular physiology); however, the identity of these ion channels has remained elusive. We previously identified Piezo1 and Piezo2 as mechanically activated cation channels that are expressed in many mechanosensitive cell types. Here, we show that Piezo1 is expressed in endothelial cells of developing blood vessels in mice. Piezo1-deficient embryos die at midgestation with defects in vascular remodeling, a process critically influenced by blood flow. We demonstrate that Piezo1 is activated by shear stress, the major type of mechanical force experienced by endothelial cells in response to blood flow. Furthermore, loss of Piezo1 in endothelial cells leads to deficits in stress fiber and cellular orientation in response to shear stress, linking Piezo1 mechanotransduction to regulation of cell morphology. These findings highlight an essential role of mammalian Piezo1 in vascular development during embryonic development.
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              Atherosclerosis: Process, Indicators, Risk Factors and New Hopes

              Background: Atherosclerosis is the major cause of morbidities and mortalities worldwide. In this study we aimed to review the mechanism of atherosclerosis and its risk factors, focusing on new findings in atherosclerosis markers and its risk factors. Furthermore, the role of antioxidants and medicinal herbs in atherosclerosis and endothelial damage has been discussed and a list of important medicinal plants effective in the treatment and prevention of hyperlipidemia and atherosclerosis is presented. Methods: The recently published papers about atherosclerosis pathogenesis and herbal medicines effective in the treatment and prevention of hyperlipidemia and atherosclerosis were searched. Results: Inflammation has a crucial role in pathogenesis of atherosclerosis. The disease is accompanied by excessive fibrosis of the intima, fatty plaques formation, proliferation of smooth muscle cells, and migration of a group of cells such as monocytes, T cells, and platelets which are formed in response to inflammation. The oxidation of low density lipoprotein (LDL) to Ox-LDL indicates the first step of atherosclerosis in cardiovascular diseases. Malondialdehyde factor shows the level of lipoperoxidation and is a sign of increased oxidative pressure and cardiovascular diseases. In special pathological conditions such as severe hypercholesterolemia, peroxynitrite concentration increases and atherosclerosis and vascular damage are intensified. Medicinal plants have shown to be capable of interacting these or other pathogenesis factors to prevent atherosclerosis. Conclusions: The pathogenesis factors involved in atherosclerosis have recently been cleared and the discovery of these factors has brought about new hopes for better prevention and treatment of atherosclerosis.
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                Author and article information

                Contributors
                Journal
                APL Bioeng
                APL Bioeng
                ABPID9
                APL Bioengineering
                AIP Publishing LLC
                2473-2877
                March 2020
                20 February 2020
                20 February 2020
                : 4
                : 1
                : 010904
                Affiliations
                [1 ]Department of Medicine, University of California , San Diego, California 92093, USA
                [2 ]Department of Pediatrics, Stanford University School of Medicine , Stanford, California 94305, USA
                [3 ]Department of Health Sciences, Victor Valley College , Victorville, California 92395, USA
                [4 ]Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope , California 91010, USA
                Author notes
                [a) ] Author to whom correspondence should be addressed: brgongol@ 123456health.ucsd.edu
                Author information
                https://orcid.org/0000-0003-0035-0185
                https://orcid.org/0000-0001-9627-613X
                Article
                1.5129563 APB19-PS-00108
                10.1063/1.5129563
                7032971
                32095737
                7dfb170a-d5c9-40d3-a08d-f2655b96473d
                © Author(s).

                2473-2877/2020/4(1)/010904/8

                All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 01 October 2019
                : 19 January 2020
                Page count
                Pages: 8
                Funding
                Funded by: Ella Fitzgerald Foundation
                Award ID: Ella Fitzgerald Foundation
                Funded by: National Heart, Lung, and Blood Institute https://doi.org/10.13039/100000050
                Award ID: R00HL122368
                Funded by: National Heart, Lung, and Blood Institute https://doi.org/10.13039/100000050
                Award ID: R01HL 145170
                Funded by: National Heart, Lung, and Blood Institute https://doi.org/10.13039/100000050
                Award ID: R01HL108735
                Funded by: National Heart, Lung, and Blood Institute https://doi.org/10.13039/100000050
                Award ID: R01HL089940
                Funded by: National Heart, Lung, and Blood Institute https://doi.org/10.13039/100000050
                Award ID: R01HL106579
                Funded by: National Heart, Lung, and Blood Institute https://doi.org/10.13039/100000050
                Award ID: 5T32HL134632-02 (MPI)
                Funded by: National Heart, Lung, and Blood Institute https://doi.org/10.13039/100000050
                Award ID: 5T32HL098049-10
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