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Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China (S.X., I.I., X.Z., S.L., J.W.); Sunshine Coast Health Institute, University of the Sunshine Coast, Birtinya, Australia (P.J.L.); School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, Australia (P.J.L., D.K.); Department of Medical Biotechnology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); The Research Center of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou, China (Z.L., P.L.); College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China (J.H.); Department of Bioengineering, Northeastern University, Boston, Massachusetts (I.C.H., E.E.E.); Department of Chemical Engineering, Northeastern University, Boston, Massachusetts (E.E.E.); Department of Neuroscience, Albert Einstein College of Medicine, New York, New York (E.E.E.); Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio (S.J.C.); and ARC Centre for Personalised Therapeutics Technologies, Department of Biochemistry and Pharmacology, School of Biomedical Science, University of Melbourne, Parkville, Victoria, Australia (A.G.S.)
Published: July 2021
AI Article Synopsis
Article Abstract
The endothelium, a cellular monolayer lining the blood vessel wall, plays a critical role in maintaining multiorgan health and homeostasis. Endothelial functions in health include dynamic maintenance of vascular tone, angiogenesis, hemostasis, and the provision of an antioxidant, anti-inflammatory, and antithrombotic interface. Dysfunction of the vascular endothelium presents with impaired endothelium-dependent vasodilation, heightened oxidative stress, chronic inflammation, leukocyte adhesion and hyperpermeability, and endothelial cell senescence. Recent studies have implicated altered endothelial cell metabolism and endothelial-to-mesenchymal transition as new features of endothelial dysfunction. Endothelial dysfunction is regarded as a hallmark of many diverse human panvascular diseases, including atherosclerosis, hypertension, and diabetes. Endothelial dysfunction has also been implicated in severe coronavirus disease 2019. Many clinically used pharmacotherapies, ranging from traditional lipid-lowering drugs, antihypertensive drugs, and antidiabetic drugs to proprotein convertase subtilisin/kexin type 9 inhibitors and interleukin 1 monoclonal antibodies, counter endothelial dysfunction as part of their clinical benefits. The regulation of endothelial dysfunction by noncoding RNAs has provided novel insights into these newly described regulators of endothelial dysfunction, thus yielding potential new therapeutic approaches. Altogether, a better understanding of the versatile (dys)functions of endothelial cells will not only deepen our comprehension of human diseases but also accelerate effective therapeutic drug discovery. In this review, we provide a timely overview of the multiple layers of endothelial function, describe the consequences and mechanisms of endothelial dysfunction, and identify pathways to effective targeted therapies. SIGNIFICANCE STATEMENT: The endothelium was initially considered to be a semipermeable biomechanical barrier and gatekeeper of vascular health. In recent decades, a deepened understanding of the biological functions of the endothelium has led to its recognition as a ubiquitous tissue regulating vascular tone, cell behavior, innate immunity, cell-cell interactions, and cell metabolism in the vessel wall. Endothelial dysfunction is the hallmark of cardiovascular, metabolic, and emerging infectious diseases. Pharmacotherapies targeting endothelial dysfunction have potential for treatment of cardiovascular and many other diseases.
