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Brain Endothelium in Health and Disease

Am J Pathol 2021 Mar 10 ENDOTHELIAL CONTROL OF CEREBRAL BLOOD FLOW Julianne W Ashby 1, Julia J Mack 2 Affiliations

  • 1 Department of Medicine, Division of Cardiology, University of California, Los Angeles.

  • 2 Department of Medicine, Division of Cardiology, University of California, Los Angeles. Electronic address:

Abstract Since constant perfusion of blood throughout the brain is critical for neuronal health, the regulation of cerebral blood flow is complex and highly controlled. Regulation of flow is controlled, in part, by the cerebral endothelium. In this review, multiple modes of endothelium-derived blood flow regulation will be discussed, including chemical control of vascular tone, heterotypic and homotypic cell-cell interactions, second messenger signaling and cellular response to physical forces and inflammatory mediators. Because cerebral small vessel disease is often associated with endothelial dysfunction and a compromised blood-brain barrier, understanding the endothelial factors that regulate vessel function to maintain cerebral blood flow and prevent vascular permeability will provide insights into disease prevention and treatment. Copyright © 2021. Published by Elsevier Inc.

Figure 2 Characteristics of the Endothelium in Health and Disease. With the onset of pathological conditions, endothelial cells undergo compensatory actions in response to circulating immune cells, blood borne agents (i.e. Bradykinin and Histamine), inflammatory cytokines (i.e. Interleukin) and macromolecules (i.e amyloid-β). Endothelial cells upregulate the expression of surface adhesion proteins ICAM-1 and VCAM-1 that enable binding of immune cells and further promotes endothelial activation. Endothelial cells also express the receptor for AGE (RAGE), a member of the immunoglobulin superfamily of cell surface molecules, that promotes the entry of amyloid-β. At the intracellular level, COX-2 sustains an inflammatory state by the release of Prostaglandin E2 (PGE2) and reactive oxygen species (ROS). In pathological conditions EDHF induces relaxation of the smooth muscle while endothelin-1 (ET-1) promotes vasoconstriction through binding to ETA receptors on the vascular smooth muscle cell (VSMC). Conversely, ET-1 can induce smooth muscle relaxation via binding on ETB receptors on the endothelium. In a healthy state, endothelial nitric oxide synthase (eNOS) activity is in part regulated by blood flow forces and Ca2+ activity to produce the important vasodilator nitric oxide (NO) and ensure proper vascular tone. Mechanisms that protect the endothelium include mechanosensitive ion channels (i.e. TRPV4), transporters of cell metabolites and nutrients (i.e. ABC Transporters), cell surface mechanotransducers (i.e. Primary Cilia), tight junctions and the protective coating of the endothelial glycocalyx. Loss of these attributes, as indicated by the dashed line, can lead to endothelial dysfunction and the evolution of cerebral small vessel disease.


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