Examine individual changes

'{{Short description|Layer of cells that lining inner surface of blood vessels}} {{about|the lining of blood and lymphatic vessels|the endothelium of the cornea|corneal endothelium}} {{More citations needed|date=April 2020}} {{Infobox cell | Name = Endothelium | Latin = | Image = Endotelijalna ćelija.jpg | Caption = Diagram showing the location of endothelial cells | Image2 = Microvessel.jpg | Caption2 = [[Transmission electron microscopy|Transmission]] [[Micrograph|electron micrograph]] of a [[microvessel]] showing endothelial cells, which encircle an [[Red blood cell|erythrocyte]] (E), forming the innermost layer of the vessel, the [[tunica intima]]. | Precursor = | System = [[Circulatory system]] | Location = Lining of the inner surface of [[blood vessel]]s and [[lymphatic vessel]]s }} The '''endothelium''' is a single layer of [[squamous epithelial cell|squamous]] '''endothelial cells''' that line the interior surface of [[blood vessel]]s, and [[lymphatic vessel]]s.<ref name="ReferenceA">{{DorlandsDict|three/000035470|Endothelium}}</ref> The endothelium forms an interface between circulating [[blood]] or [[lymph]] in the [[lumen (anatomy)|lumen]] and the rest of the vessel wall. Endothelial cells form the barrier between vessels and tissue and control the flow of substances and fluid into and out of a tissue. Endothelial cells in direct contact with blood are called vascular endothelial cells whereas those in direct contact with [[lymph]] are known as lymphatic endothelial cells. Vascular endothelial cells line the entire [[circulatory system]], from the [[heart]] to the smallest [[capillaries]]. These cells have unique functions that include [[ultrafiltration|fluid filtration]], such as in the [[glomerulus]] of the kidney, [[muscle tone|blood vessel tone]], [[hemostasis]], [[neutrophil]] recruitment, and hormone trafficking. Endothelium of the interior surfaces of the heart chambers is called [[endocardium]]. An impaired function can lead to serious health issues throughout the body. == Structure == The endothelium is a thin layer of single flat ([[squamous epithelial cell|squamous]]) cells that line the interior surface of [[blood vessel]]s and [[lymphatic vessel]]s.<ref name="ReferenceA"/> Endothelium is of [[mesoderm]some origin. Both blood and lymphatic [[capillaries]] are composed of a single layer of endothelial cells called a monolayer. In straight sections of a blood vessel, vascular endothelial cells typically align and elongate in the direction of fluid flow.<ref>{{cite journal | vauthors = Eskin SG, Ives CL, McIntire LV, Navarro LT | title = Response of cultured endothelial cells to steady flow | journal = Microvascular Research | volume = 28 | issue = 1 | pages = 87–94 | date = July 1984 | pmid = 6748961 | doi = 10.1016/0026-2862(84)90031-1 }}</ref><ref>{{cite journal | vauthors = Langille BL, Adamson SL | title = Relationship between blood flow direction and endothelial cell orientation at arterial branch sites in rabbits and mice | journal = Circulation Research | volume = 48 | issue = 4 | pages = 481–8 | date = April 1981 | pmid = 7460219 | doi = 10.1161/01.RES.48.4.481 | doi-access = free }}</ref> === Terminology === The [[Foundational Model of Anatomy|foundational model of anatomy]], an index of terms used to describe anatomical structures, makes a distinction between endothelial cells and [[epithelial cells]] on the basis of which tissues they develop from, and states that the presence of [[vimentin]] rather than [[keratin]] filaments separates these from epithelial cells.<ref name="urlFMA">{{cite web|url=http://bioportal.bioontology.org/ontologies/FMA/?p=classes&conceptid=http%3A%2F%2Fsig.uw.edu%2Ffma%23Endothelial_cell&jump_to_nav=true |title=Endothelial cell | work = BioPortal | publisher = Stanford University |access-date=2013-09-28 |url-status=dead |archive-url=https://web.archive.org/web/20131002075249/http://bioportal.bioontology.org/ontologies/FMA/?p=classes&conceptid=http%3A%2F%2Fsig.uw.edu%2Ffma%23Endothelial_cell&jump_to_nav=true |archive-date=2013-10-02 }}</ref> Many considered the endothelium a specialized [[epithelial]] tissue.<ref>{{cite journal|author1-link=Jason Kovacic | vauthors = Kovacic JC, Mercader N, Torres M, Boehm M, Fuster V | title = Epithelial-to-mesenchymal and endothelial-to-mesenchymal transition: from cardiovascular development to disease | journal = Circulation | volume = 125 | issue = 14 | pages = 1795–808 | date = April 2012 | pmid = 22492947 | pmc = 3333843 | doi = 10.1161/circulationaha.111.040352 }}</ref> == Function == [[File:2104 Three Major Capillary Types.jpg|thumbnail|Endothelium lines the inner wall of vessels, shown here.]] [[File:Endocardium and subendocardium histology.png|thumb|[[Histology|Microscopic view]] showing endothelium (at top) inside the [[heart]].]] The endothelium forms an interface between circulating [[blood]] or [[lymph]] in the [[lumen (anatomy)|lumen]] and the rest of the vessel wall. This forms a barrier between vessels and tissues and control the flow of substances and fluid into and out of a tissue. This controls the passage of materials and the transit of [[white blood cell]]s into and out of the bloodstream. Excessive or prolonged increases in permeability of the endothelium, as in cases of chronic inflammation, may lead to tissue swelling ([[edema]]). Altered barrier function is also implicated in cancer extravasation.<ref>{{cite journal|display-authors=6|vauthors=Escribano J, Chen MB, Moeendarbary E, Cao X, Shenoy V, Garcia-Aznar JM, Kamm RD, Spill F|date=May 2019|title=Balance of mechanical forces drives endothelial gap formation and may facilitate cancer and immune-cell extravasation|journal=PLOS Computational Biology|volume=15|issue=5|pages=e1006395|doi=10.1371/journal.pcbi.1006395|pmc=6497229|pmid=31048903|arxiv=1811.09326|bibcode=2019PLSCB..15E6395E}}</ref> Endothelial cells are involved in many other aspects of vessel function, including: * [[Coagulation|Blood clotting]] ([[thrombosis]] and [[fibrinolysis]]). The endothelium normally provides a surface on which blood does not clot, because it contains and expresses substances that prevent clotting, including [[heparan sulfate]] which acts as a [[Cofactor (biochemistry)|cofactor]] for activating [[antithrombin]], a protease that inactivates several factors in the coagulation cascade. * [[Inflammation]].<ref name="li-2016">{{cite journal | vauthors = Li X, Fang P, Li Y, Kuo YM, Andrews AJ, Nanayakkara G, Johnson C, Fu H, Shan H, Du F, Hoffman NE, Yu D, Eguchi S, Madesh M, Koch WJ, Sun J, Jiang X, Wang H, Yang X | display-authors = 6 | title = Mitochondrial Reactive Oxygen Species Mediate Lysophosphatidylcholine-Induced Endothelial Cell Activation | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 36 | issue = 6 | pages = 1090–100 | date = June 2016 | pmid = 27127201 | pmc = 4882253 | doi = 10.1161/ATVBAHA.115.306964 }}</ref> Endothelial cells actively signal to white blood cells of the immune system<ref>{{cite journal | vauthors = Vestweber D | title = How leukocytes cross the vascular endothelium | journal = Nature Reviews. Immunology | volume = 15 | issue = 11 | pages = 692–704 | date = November 2015 | pmid = 26471775 | doi = 10.1038/nri3908 | s2cid = 29703333 }}</ref> during inflammation * Formation of new blood vessels ([[angiogenesis]]). * Constriction and enlargement of the blood vessel, called [[vasoconstriction]] and [[vasodilation]], and hence the control of [[blood pressure]] ===Blood vessel formation=== The endothelium is involved in the formation of new blood vessels, called [[angiogenesis]]. {{Citation needed|date=April 2020}} Angiogenesis is a crucial process for development of organs in the embryo and fetus,<ref name=":1"/> as well as repair of damaged areas. The process is triggered by decreased tissue oxygen (hypoxia) or insufficient oxygen tension leading to the new development of blood vessels lined with endothelial cells. Angiogenesis is regulated by signals that promote and decrease the process. These pro- and antiangiogenic signals including integrins, chemokines, angiopoietins, oxygen sensing agents, junctional molecules and endogenous inhibitors.<ref name=":1">{{cite journal | vauthors = Bouïs D, Kusumanto Y, Meijer C, Mulder NH, Hospers GA | title = A review on pro- and anti-angiogenic factors as targets of clinical intervention | journal = Pharmacological Research | volume = 53 | issue = 2 | pages = 89–103 | date = February 2006 | pmid = 16321545 | doi = 10.1016/j.phrs.2005.10.006 }}</ref> [[Angiopoietin-2]] works with VEGF to facilitate cell proliferation and migration of endothelial cells. The general outline of angiogenesis is * activating signals binding to surface receptors of vascular endothelial cells. * activated endothelial cells release proteases leading to the degradation of the basement membrane * endothelial cells are freed to migrate from the existing blood vessels and begin to proliferate to form extensions towards the source of the angiogenic stimulus. === Host immune response === Endothelial cells express a variety of immune genes in an organ-specific manner.<ref name="Krausgruber_2020">{{cite journal | vauthors = Krausgruber T, Fortelny N, Fife-Gernedl V, Senekowitsch M, Schuster LC, Lercher A, Nemc A, Schmidl C, Rendeiro AF, Bergthaler A, Bock C | display-authors = 6 | title = Structural cells are key regulators of organ-specific immune responses | journal = Nature | volume = 583 | issue = 7815 | pages = 296–302 | date = July 2020 | pmid = 32612232 | doi = 10.1038/s41586-020-2424-4|pmc=7610345 | bibcode = 2020Natur.583..296K | s2cid = 220295181 | doi-access = free }}</ref> These genes include critical [[Cytokine|immune mediators]] and proteins that facilitate [[Cell signaling|cellular communication]] with hematopoietic immune cells.<ref>{{cite journal | vauthors = Armingol E, Officer A, Harismendy O, Lewis NE | title = Deciphering cell-cell interactions and communication from gene expression | journal = Nature Reviews. Genetics | date = November 2020 | volume = 22 | issue = 2 | pages = 71–88 | pmid = 33168968 | pmc = 7649713 | doi = 10.1038/s41576-020-00292-x }}</ref> Endothelial cells encode important features of the structural cell immune response in the [[epigenome]] and can therefore respond swiftly to immunological challenges. The contribution to host immunity by non-hematopoietic cells, such as endothelium, is called “structural immunity”.<ref name="Minton_2020">{{cite journal | vauthors = Minton K | title = A gene atlas of 'structural immunity' | journal = Nature Reviews. Immunology | volume = 20 | issue = 9 | pages = 518–519 | date = September 2020 | pmid = 32661408 | doi = 10.1038/s41577-020-0398-y | s2cid = 220491226 | doi-access = free }}</ref> ==Clinical significance== {{Main|Endothelial dysfunction}} [[Endothelial dysfunction]], or the loss of proper endothelial function, is a hallmark for vascular diseases, and is often regarded as a key early event in the development of [[atherosclerosis]].<ref name="botts-2021">{{cite journal | vauthors = Botts SR, Fish JE, Howe KL | title = Dysfunctional Vascular Endothelium as a Driver of Atherosclerosis: Emerging Insights Into Pathogenesis and Treatment | journal = Frontiers in Pharmacology | volume = 12 | pages = 787541 | date = December 2021 | pmid = 35002720 | pmc = 8727904 | doi = 10.3389/fphar.2021.787541 | doi-access = free }}</ref> Impaired endothelial function, causing hypertension and thrombosis, is often seen in patients with [[coronary artery disease]], [[diabetes mellitus]], [[hypertension]], [[hypercholesterolemia]], as well as in [[Tobacco smoking|smokers]]. Endothelial dysfunction has also been shown to be predictive of future adverse cardiovascular events, and is also present in inflammatory disease such as rheumatoid arthritis and systemic lupus erythematosus.{{Citation needed|date=April 2020}} Endothelial dysfunction is a result of changes in endothelial function.<ref>{{cite journal | vauthors = Iantorno M, Campia U, Di Daniele N, Nistico S, Forleo GB, Cardillo C, Tesauro M | title = Obesity, inflammation and endothelial dysfunction | journal = Journal of Biological Regulators and Homeostatic Agents | volume = 28 | issue = 2 | pages = 169–76 | date = April 2014 | pmid = 25001649 }}</ref><ref>{{cite journal | vauthors = Reriani MK, Lerman LO, Lerman A | title = Endothelial function as a functional expression of cardiovascular risk factors | journal = Biomarkers in Medicine | volume = 4 | issue = 3 | pages = 351–60 | date = June 2010 | pmid = 20550469 | pmc = 2911781 | doi = 10.2217/bmm.10.61 }}</ref> After fat ([[lipid]]) accumulation and when stimulated by inflammation, endothelial cells become activated, which is characterized by the expression of molecules such as E-selectin, VCAM-1 and ICAM-1, which stimulate the adhesion of immune cells.<ref>{{cite journal | vauthors = Lopez-Garcia E, Hu FB | title = Nutrition and the endothelium | journal = Current Diabetes Reports | volume = 4 | issue = 4 | pages = 253–9 | date = August 2004 | pmid = 15265466 | doi=10.1007/s11892-004-0076-7| s2cid = 24878288 }}</ref> Additionally, [[transcription factor]]s, which are substances which act to increase the production of proteins within cells, become activated; specifically AP-1 and [[NF-κB]], leading to increased expression of cytokines such as [[Interleukin-1 family|IL-1]], [[Tumor necrosis factor alpha|TNFα]] and [[Interferon gamma|IFNγ]], which promotes inflammation.<ref>{{cite journal | vauthors = Blake GJ, Ridker PM | title = Inflammatory bio-markers and cardiovascular risk prediction | journal = Journal of Internal Medicine | volume = 252 | issue = 4 | pages = 283–94 | date = October 2002 | pmid = 12366601 | doi=10.1046/j.1365-2796.2002.01019.x| s2cid = 26400610 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Mizuno Y, Jacob RF, Mason RP | title = Inflammation and the development of atherosclerosis | journal = Journal of Atherosclerosis and Thrombosis | volume = 18 | issue = 5 | pages = 351–8 | date = 2011 | pmid = 21427505 | doi=10.5551/jat.7591| doi-access = free }}</ref> This state of endothelial cells promotes accumulation of lipids and lipoproteins in the intima, leading to atherosclerosis, and the subsequent recruitment of white blood cells and platelets, as well as proliferation of smooth muscle cells, leading to the formation of a fatty streak. The lesions formed in the intima, and persistent inflammation lead to desquamation of endothelium, which disrupts the endothelial barrier, leading to injury and consequent dysfunction.<ref>{{cite journal | vauthors = Mäyränpää MI, Heikkilä HM, Lindstedt KA, Walls AF, Kovanen PT | title = Desquamation of human coronary artery endothelium by human mast cell proteases: implications for plaque erosion | journal = Coronary Artery Disease | volume = 17 | issue = 7 | pages = 611–21 | date = November 2006 | pmid = 17047445 | doi = 10.1097/01.mca.0000224420.67304.4d | s2cid = 1884596 }}</ref> In contrast, inflammatory stimuli also activate NF-κB-induced expression of the deubiquitinase A20 ([[TNFAIP3]]), which has been shown to intrinsically repair the endothelial barrier.<ref name="Soni_2018">{{cite journal | vauthors = Soni D, Wang DM, Regmi SC, Mittal M, Vogel SM, Schlüter D, Tiruppathi C | title = Deubiquitinase function of A20 maintains and repairs endothelial barrier after lung vascular injury | journal = Cell Death Discovery | volume = 4 | issue = 60 | pages = 60| date = May 2018 | pmid = 29796309| pmc =5955943 | doi = 10.1038/s41420-018-0056-3}}</ref> One of the main mechanisms of endothelial dysfunction is the diminishing of [[nitric oxide]], often due to high levels of [[asymmetric dimethylarginine]], which interfere with the normal [[Arginine|L-arginine]]-stimulated [[Nitric oxide synthase|nitric oxide synthesis]] and so leads to hypertension. The most prevailing mechanism of endothelial dysfunction is an increase in [[reactive oxygen species]], which can impair nitric oxide production and activity via several mechanisms.<ref name="pmid15643116">{{cite journal | vauthors = Deanfield J, Donald A, Ferri C, Giannattasio C, Halcox J, Halligan S, Lerman A, Mancia G, Oliver JJ, Pessina AC, Rizzoni D, Rossi GP, Salvetti A, Schiffrin EL, Taddei S, Webb DJ | title = Endothelial function and dysfunction. Part I: Methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension | journal = Journal of Hypertension | volume = 23 | issue = 1 | pages = 7–17 | date = January 2005 | pmid = 15643116 | doi = 10.1097/00004872-200501000-00004 }}</ref> The signalling protein [[ERK5]] is essential for maintaining normal endothelial cell function.<ref name="pmid19909257">{{cite journal | vauthors = Roberts OL, Holmes K, Müller J, Cross DA, Cross MJ | title = ERK5 and the regulation of endothelial cell function | journal = Biochemical Society Transactions | volume = 37 | issue = Pt 6 | pages = 1254–9 | date = December 2009 | pmid = 19909257 | doi = 10.1042/BST0371254 }}</ref> A further consequence of damage to the endothelium is the release of pathological quantities of [[von Willebrand factor]], which promote platelet aggregation and adhesion to the subendothelium, and thus the formation of potentially fatal thrombi. [[Angiosarcoma]] is cancer of the endothelium and is rare with only 300 cases per year in the US.<ref>{{Cite web|date=2019-02-27|title=Angiosarcoma - National Cancer Institute|url=https://www.cancer.gov/pediatric-adult-rare-tumor/rare-tumors/rare-vascular-tumors/angiosarcoma|access-date=2021-08-10|website=www.cancer.gov|language=en}}</ref> However it generally has poor prognosis with a five-year survival rate of 35%.<ref>{{Cite journal|last1=Young|first1=Robin J.|last2=Brown|first2=Nicola J.|last3=Reed|first3=Malcolm W.|last4=Hughes|first4=David|last5=Woll|first5=Penella J.|date=October 2010|title=Angiosarcoma|url=https://pubmed.ncbi.nlm.nih.gov/20537949/|journal=The Lancet. Oncology|volume=11|issue=10|pages=983–991|doi=10.1016/S1470-2045(10)70023-1|issn=1474-5488|pmid=20537949}}</ref> === Research === === Endothelium in cancer === It has been recognised that endothelial cells building tumour vasculature have distinct morphological characteristics, different origin compared to physiological endothelium, and distinct molecular signature, which gives an opportunity for implementation of new biomarkers of tumour angiogenesis and could provide new anti-angiogenic druggable targets.<ref>{{Citation |last=Milosevic |first=Vladan |title=Molecular Phenotypes of Endothelial Cells in Malignant Tumors |date=2022 |url=https://doi.org/10.1007/978-3-030-98950-7_3 |work=Biomarkers of the Tumor Microenvironment |pages=31–52 |editor-last=Akslen |editor-first=Lars A. |place=Cham |publisher=Springer International Publishing |language=en |doi=10.1007/978-3-030-98950-7_3 |isbn=978-3-030-98950-7 |access-date=2022-07-13 |last2=Edelmann |first2=Reidunn J. |last3=Fosse |first3=Johanna Hol |last4=Östman |first4=Arne |last5=Akslen |first5=Lars A. |editor2-last=Watnick |editor2-first=Randolph S.}}</ref> In cancer therapy the development and delivery of [[Angiogenesis inhibitor|anti-angiogenic drugs]] is a very promising path and restoring vascular homeostasis holds great potential for the treatment of ischemic tissue diseases <ref name=":0">{{cite journal | vauthors = Van Hove AH, Benoit DS | title = Depot-Based Delivery Systems for Pro-Angiogenic Peptides: A Review | journal = Frontiers in Bioengineering and Biotechnology | volume = 3 | pages = 102 | date = 2015 | pmid = 26236708 | pmc = 4504170 | doi = 10.3389/fbioe.2015.00102 | doi-access = free }}</ref> === Endothelium in Covid-19 === In April 2020, the presence of viral elements in endothelial cells of 3 patients who had died of [[Coronavirus disease 2019|COVID-19]] was reported for the first time. The researchers from the [[University of Zurich]] and [[Harvard Medical School]] considered these findings to be a sign of a general [[endotheliitis]] in different organs, an inflammatory response of the endothelium to the infection that can lead or at least contribute to multi-organ failure in Covid-19 patients with comorbidities such as diabetes mellitus, hypertension and cardiovascular disease.<ref name="pmid32325026">{{cite journal | vauthors = Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, Mehra MR, Schuepbach RA, Ruschitzka F, Moch H | title = Endothelial cell infection and endotheliitis in COVID-19 | journal = Lancet | volume = 395 | issue = 10234 | pages = 1417–1418 | date = May 2020 | pmid = 32325026 | doi = 10.1016/S0140-6736(20)30937-5 | pmc = 7172722 }}</ref><ref>{{cite journal |vauthors=Sardu C, Gambardella J, Morelli MB, Wang X, Marfella R, Santulli G |title=Hypertension, Thrombosis, Kidney Failure, and Diabetes: Is COVID-19 an Endothelial Disease? A Comprehensive Evaluation of Clinical and Basic Evidence |journal=J Clin Med |volume=9 |issue=5 |date=May 2020 |page=1417 |pmid=32403217 |pmc=7290769 |doi=10.3390/jcm9051417 |url=|doi-access=free }}</ref> ==History== In 1958, A. S. Todd of the [[University of St Andrews]] demonstrated that endothelium in human blood vessels have fibrinolytic activity.<ref>{{cite journal | vauthors = Todd AS | title = Fibrinolysis autographs | journal = Nature | volume = 181 | issue = 4607 | pages = 495–6 | date = February 1958 | pmid = 13517190 | doi = 10.1038/181495b0 | bibcode = 1958Natur.181..495T | s2cid = 4219257 | eissn = 1476-4687 }}</ref><ref>{{cite journal | vauthors = Todd AS | title = Localization of fibrinolytic activity in tissues | journal = British Medical Bulletin | volume = 20 | issue = 3 | pages = 210–2 | date = September 1964 | pmid = 14209761 | doi = 10.1093/oxfordjournals.bmb.a070333 | eissn = 1471-8391 }}</ref> == See also == {{columns-list|colwidth=22em| * [[Apelin]] * [[Caveolae]] * [[Cellular dewetting]] * [[Endothelial activation]] * [[Endothelial microparticle]] * [[Endothelial progenitor cell]] * [[Endothelium-derived relaxing factor]] (EDRF) * [[Robert F. Furchgott]] (1998 Nobel prize for discovery of EDRF) * [[Platelet activation]] * [[Susac's syndrome]] * [[Tunica intima]] * [[VE-cadherin]] * [[Weibel–Palade body]] * [[Angiocrine growth factors]] * [[Endothelial Cell Tropism]] }} == References == {{Reflist|30em}} == External links == * {{UCDavisOrganology|Circulatory/vessels/capillaries1/capillaries3}}, "Capillaries, non-fenestrated (EM, Low)" * {{BUHistology|21402ooa}} * [http://essuir.sumdu.edu.ua/handle/123456789/2689 Endothelium and inflammation] * [http://courses.washington.edu/conj/bloodcells/platelets.htm Platelet Activation], [[University of Washington]] == Further reading == * Milosevic, V., Edelmann, R.J., Fosse, J.H., Östman, A., Akslen, L.A. (2022). [https://link.springer.com/chapter/10.1007/978-3-030-98950-7_3 Molecular Phenotypes of Endothelial Cells in Malignant Tumors. In: Akslen, L.A., Watnick, R.S. (eds) Biomarkers of the Tumor Microenvironment]. Springer, Cham. https://doi.org/10.1007/978-3-030-98950-7_3 {{Epithelium and epithelial tissue}} {{Cardiovascular system}} {{Authority control}} [[Category:Angiology]] [[Category:Tissues (biology)]]'