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      Endothelial Cell Mechano-Metabolomic Coupling to Disease States in the Lung Microvasculature

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          Abstract

          Lungs are the most vascular part of humans, accepting the totality of cardiac output in a volume much smaller than the body itself. Due to this cardiac output, the lung microvasculature is subject to mechanical forces including shear stress and cyclic stretch that vary with the cardiac and breathing cycle. Vessels are surrounded by extracellular matrix which dictates the stiffness which endothelial cells also sense and respond to. Shear stress, stiffness, and cyclic stretch are known to influence endothelial cell state. At high shear stress, endothelial cells exhibit cell quiescence marked by low inflammatory markers and high nitric oxide synthesis, whereas at low shear stress, endothelial cells are thought to “activate” into a pro-inflammatory state and have low nitric oxide. Shear stress' profound effect on vascular phenotype is most apparent in the arterial vasculature and in the pathophysiology of vascular inflammation. To conduct the flow of blood from the right heart, the lung microvasculature must be rigid yet compliant. It turns out that excessive substrate rigidity or stiffness is important in the development of pulmonary hypertension and chronic fibrosing lung diseases via excessive cell proliferation or the endothelial-mesenchymal transition. Recently, a new body of literature has evolved that couples mechanical sensing to endothelial phenotypic changes through metabolic signaling in clinically relevant contexts such as pulmonary hypertension, lung injury syndromes, as well as fibrosis, which is the focus of this review. Stretch, like flow, has profound effect on endothelial phenotype; metabolism studies due to stretch are in their infancy.

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          Most cited references185

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          Hypoxia-induced pulmonary vascular remodeling: cellular and molecular mechanisms.

          Chronic hypoxic exposure induces changes in the structure of pulmonary arteries, as well as in the biochemical and functional phenotypes of each of the vascular cell types, from the hilum of the lung to the most peripheral vessels in the alveolar wall. The magnitude and the specific profile of the changes depend on the species, sex, and the developmental stage at which the exposure to hypoxia occurred. Further, hypoxia-induced changes are site specific, such that the remodeling process in the large vessels differs from that in the smallest vessels. The cellular and molecular mechanisms vary and depend on the cellular composition of vessels at particular sites along the longitudinal axis of the pulmonary vasculature, as well as on local environmental factors. Each of the resident vascular cell types (ie, endothelial, smooth muscle, adventitial fibroblast) undergo site- and time-dependent alterations in proliferation, matrix protein production, expression of growth factors, cytokines, and receptors, and each resident cell type plays a specific role in the overall remodeling response. In addition, hypoxic exposure induces an inflammatory response within the vessel wall, and the recruited circulating progenitor cells contribute significantly to the structural remodeling and persistent vasoconstriction of the pulmonary circulation. The possibility exists that the lung or lung vessels also contain resident progenitor cells that participate in the remodeling process. Thus the hypoxia-induced remodeling of the pulmonary circulation is a highly complex process where numerous interactive events must be taken into account as we search for newer, more effective therapeutic interventions. This review provides perspectives on each of the aforementioned areas.
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            YAP/TAZ upstream signals and downstream responses

            Cell behavior is strongly influenced by physical, mechanical contacts between cells and their extracellular matrix. We review how the transcriptional regulators YAP/TAZ integrate mechanical cues with the response to soluble signals and metabolic pathways to control multiple aspects of cell behavior, including proliferation, cell plasticity and stemness essential for tissue regeneration. Corruption of cell-environment interplay leads to aberrant YAP/TAZ activation that is instrumental for multiple diseases, including cancer.
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              Fatty acid carbon is essential for dNTP synthesis in endothelial cells

              The metabolism of endothelial cells (ECs) during vessel sprouting remains poorly studied. Here, we report that endothelial loss of CPT1a, a rate-limiting enzyme of fatty acid oxidation (FAO), caused vascular sprouting defects due to impaired proliferation, not migration of ECs. Reduction of FAO in ECs did not cause energy depletion or disturb redox homeostasis, but impaired de novo nucleotide synthesis for DNA replication. Isotope labeling studies in control ECs showed that fatty acid carbons substantially replenished the Krebs cycle, and were incorporated into aspartate (a nucleotide precursor), uridine monophosphate (a precursor of pyrimidine nucleoside triphosphates) and DNA. CPT1a silencing reduced these processes and depleted EC stores of aspartate and deoxyribonucleoside triphosphates. Acetate (metabolized to acetyl-CoA, thereby substituting for the depleted FAO-derived acetyl-CoA) or a nucleoside mix rescued the phenotype of CPT1a-silenced ECs. Finally, CPT1 blockade inhibited pathological ocular angiogenesis, suggesting a novel strategy for blocking angiogenesis.
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                Author and article information

                Contributors
                Journal
                Front Bioeng Biotechnol
                Front Bioeng Biotechnol
                Front. Bioeng. Biotechnol.
                Frontiers in Bioengineering and Biotechnology
                Frontiers Media S.A.
                2296-4185
                19 July 2019
                2019
                : 7
                Affiliations
                [1] 1Section of Pulmonary and Critical Care, Department of Medicine, University of Chicago , Chicago, IL, United States
                [2] 2Department of Anesthesia, University of Maryland , Baltimore, MD, United States
                Author notes

                Edited by: Martijn van Griensven, Technical University of Munich, Germany

                Reviewed by: Duncan J. Stewart, University of Ottawa, Canada; Rebecca Heise, Virginia Commonwealth University, United States; Paul Brian Dieffenbach, Brigham and Women's Hospital and Harvard Medical School, United States

                *Correspondence: David Wu dwu1@ 123456medicine.bsd.uchicago.edu

                This article was submitted to Tissue Engineering and Regenerative Medicine, a section of the journal Frontiers in Bioengineering and Biotechnology

                Article
                10.3389/fbioe.2019.00172
                6658821
                d28a36a4-92bf-4501-a956-c569853b19e5
                Copyright © 2019 Wu and Birukov.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 258, Pages: 18, Words: 17619
                Funding
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: HL145113
                Categories
                Bioengineering and Biotechnology
                Review

                metabolism,pulmonary,endothelial (dys)function,microvasculature,endothelial mesenchymal transition

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