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However, it is still not clear whether in atherosclerosis, glycocalyx injury precedes other features of endothelial dysfunction or these events coincide.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">Herein, we demonstrate that in 4\u2010 to 8\u2010week\u2010old apolipoprotein E\/low\u2010density lipoprotein receptor\u2010deficient mice, at the stage before development of atherosclerotic plaques, impaired acetylcholine\u2010induced vasodilation, reduced NO production in aorta, and increased endothelial permeability were all observed; however, flow\u2010mediated dilation in the femoral artery was fully preserved. In 4\u2010week\u2010old mice, glycocalyx coverage was reduced and endothelial stiffness was increased, whereas glycocalyx length was significantly decreased at 8\u00a0weeks of age. Early changes in endothelial function were also featured by increased plasma concentration of biomarkers of glycocalyx disruption (endocan), biomarkers of endothelial inflammation (soluble vascular cell adhesion molecule 1), increased vascular permeability (angiopoietin 2), and alterations in hemostasis (tissue plasminogen activator and plasminogen activator inhibitor 1). In 28\u2010week\u2010old mice, at the stage of advanced atherosclerotic plaque development, impaired NO production and nearly all other features of endothelial dysfunction were changed to a similar extent, compared with the preatherosclerotic plaque phase. The exceptions were the occurrence of acetylcholine\u2010induced vasoconstriction in the aorta and brachiocephalic artery, impaired flow\u2010mediated vasodilation in the femoral artery, and further reduction of glycocalyx length and coverage with a concomitant further increase in endothelial permeability.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">In conclusion, even at the early stage before the development of atherosclerotic plaques, endothelial dysfunction is a complex multifactorial response that has not been previously appreciated.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.118.011171","type":"journal-article","created":{"date-parts":[[2019,3,14]],"date-time":"2019-03-14T09:00:19Z","timestamp":1552554019000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":101,"title":["Degradation of Glycocalyx and Multiple Manifestations of Endothelial Dysfunction Coincide in the Early Phase of Endothelial Dysfunction Before Atherosclerotic Plaque Development in Apolipoprotein E\/Low\u2010Density Lipoprotein Receptor\u2010Deficient Mice"],"prefix":"10.1161","volume":"8","author":[{"given":"Anna","family":"Bar","sequence":"first","affiliation":[{"name":"Jagiellonian University Jagiellonian Centre for Experimental Therapeutics Krakow Poland"},{"name":"Jagiellonian University Medical College Faculty of Medicine Chair of Pharmacology  Krakow Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Targosz\u2010Korecka","sequence":"additional","affiliation":[{"name":"Center for Nanometer\u2010Scale Science and Advanced Materials NANOSAM Faculty of Physics, Astronomy and Applied Computer Science  Krakow Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Suraj","sequence":"additional","affiliation":[{"name":"Jagiellonian University Jagiellonian Centre for Experimental Therapeutics Krakow Poland"},{"name":"Faculty of Pharmacy Chair and Department of Toxicology Krakow Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bartosz","family":"Proniewski","sequence":"additional","affiliation":[{"name":"Jagiellonian University Jagiellonian Centre for Experimental Therapeutics Krakow Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Jasztal","sequence":"additional","affiliation":[{"name":"Jagiellonian University Jagiellonian Centre for Experimental Therapeutics Krakow Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brygida","family":"Marczyk","sequence":"additional","affiliation":[{"name":"Jagiellonian University Jagiellonian Centre for Experimental Therapeutics Krakow Poland"},{"name":"Jagiellonian University Medical College Faculty of Medicine Chair of Pharmacology  Krakow Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Sternak","sequence":"additional","affiliation":[{"name":"Jagiellonian University Jagiellonian Centre for Experimental Therapeutics Krakow Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Przyby\u0142o","sequence":"additional","affiliation":[{"name":"Wroclaw University of Science and Technology Department of Biomedical Engineering  Wroclaw Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Kurpi\u0144ska","sequence":"additional","affiliation":[{"name":"Jagiellonian University Jagiellonian Centre for Experimental Therapeutics Krakow Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Walczak","sequence":"additional","affiliation":[{"name":"Jagiellonian University Jagiellonian Centre for Experimental Therapeutics Krakow Poland"},{"name":"Faculty of Pharmacy Chair and Department of Toxicology Krakow Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata B.","family":"Kostogrys","sequence":"additional","affiliation":[{"name":"University of Agriculture H. 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