TY - JOUR
T1 - Diverse ultrastructural landscape of atherosclerotic endothelium
AU - Kluza, Ewelina
AU - Beldman, Thijs J.
AU - Shami, Annelie
AU - Scholl, Edwin R.
AU - Malinova, Tsveta S.
AU - Grootemaat, Anita E.
AU - van der Wel, Nicole N.
AU - Gonçalves, Isabel
AU - Huveneers, Stephan
AU - Mulder, Willem J. M.
AU - Lutgens, Esther
N1 - Funding Information: We acknowledge the support from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organization for Health Research, and Development and the Royal Netherlands Academy of Sciences for the GENIUS-II project ?Generating the best evidence-based pharmaceutical targets for atherosclerosis? (CVON2017-20 to E.L.); the Deutsche Forschungsgemeinschaft (CRC 1123 to E.L., project A5); the Netherlands Organization for Scientific Research (NWO) for Vici grant to E.L. (016.130.676), Vici grant to W.J.M.M (016.176.622), Vidi grant to W.J.M.M (016.136.324) and S.H (016.156.327), STW grant (15851); the European Research Council (ERC consolidator grant to E.L), Swedish Research Council, Sk?ne University Hospital, Lund University Diabetes Centre-IRC to I.G., and Swedish Heart and Lung Foundation to I.G. and A.S. This work was financially supported by National Institutes of Health grants R01 HL118440 (W.J.M.M.), R01 HL125703 (W.J.M.M.), R01 CA155432 (W.J.M.M.). The authors also thank Sensi Pharma BV for their funding. Funding Information: We acknowledge the support from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres , the Netherlands Organization for Health Research, and Development and the Royal Netherlands Academy of Sciences for the GENIUS-II project ‘Generating the best evidence-based pharmaceutical targets for atherosclerosis’ (CVON2017-20 to E.L.); the Deutsche Forschungsgemeinschaft ( CRC 1123 to E.L., project A5); the Netherlands Organization for Scientific Research (NWO) for Vici grant to E.L. ( 016.130.676 ), Vici grant to W.J.M.M (016.176.622), Vidi grant to W.J.M.M (016.136.324) and S.H (016.156.327), STW grant (15851); the European Research Council (ERC consolidator grant to E.L), Swedish Research Council , Skåne University Hospital, Lund University Diabetes Centre-IRC to I.G., and Swedish Heart and Lung Foundation to I.G. and A.S. This work was financially supported by National Institutes of Health grants R01 HL118440 (W.J.M.M.), R01 HL125703 (W.J.M.M.), R01 CA155432 (W.J.M.M.). The authors also thank Sensi Pharma BV for their funding. Publisher Copyright: © 2021 The Authors
PY - 2021/12/1
Y1 - 2021/12/1
N2 - Background and aims: The endothelium plays a major role in atherosclerosis, yet the endothelial plaque surface is a largely uncharted territory. Here we hypothesize that atherosclerosis-driven remodeling of the endothelium is a dynamic process, involving both damaging and regenerative mechanisms. Methods: Using scanning electron microscopy (SEM) and immuno-SEM, we studied endothelial junction ultrastructure, endothelial openings and immune cell-endothelium interactions in eight apoe−/− mice and two human carotid plaques. Results: The surface of early mouse plaques (n = 11) displayed a broad range of morphological alterations, including junctional disruptions and large transcellular endothelial pores with the average diameter between 0.6 and 3 μm. The shoulder region of advanced atherosclerotic lesions (n = 7) had a more aggravated morphology with 8 μm-size paracellular openings at two-fold higher density. In contrast, the central apical surface of advanced plaques, i.e., the plaque body (n = 7), displayed endothelial normalization, as shown by a significantly higher frequency of intact endothelial junctions and a lower incidence of paracellular pores. This normalized endothelial phenotype correlated with low immune cell density (only 5 cells/mm2). The human carotid plaque surface (n = 2) displayed both well-organized and disrupted endothelium with similar features as described above. In addition, they were accompanied by extensive thrombotic areas. Conclusions: Our study unveils the spectrum of endothelial abnormalities associated with the development of atherosclerosis. These were highly abundant in early lesions and in the shoulder region of advanced plaques, while normalized at the advanced plaque's body. Similar endothelial features were observed in human atherosclerotic plaques, underlining the versatility of endothelial transformations in atherosclerosis.
AB - Background and aims: The endothelium plays a major role in atherosclerosis, yet the endothelial plaque surface is a largely uncharted territory. Here we hypothesize that atherosclerosis-driven remodeling of the endothelium is a dynamic process, involving both damaging and regenerative mechanisms. Methods: Using scanning electron microscopy (SEM) and immuno-SEM, we studied endothelial junction ultrastructure, endothelial openings and immune cell-endothelium interactions in eight apoe−/− mice and two human carotid plaques. Results: The surface of early mouse plaques (n = 11) displayed a broad range of morphological alterations, including junctional disruptions and large transcellular endothelial pores with the average diameter between 0.6 and 3 μm. The shoulder region of advanced atherosclerotic lesions (n = 7) had a more aggravated morphology with 8 μm-size paracellular openings at two-fold higher density. In contrast, the central apical surface of advanced plaques, i.e., the plaque body (n = 7), displayed endothelial normalization, as shown by a significantly higher frequency of intact endothelial junctions and a lower incidence of paracellular pores. This normalized endothelial phenotype correlated with low immune cell density (only 5 cells/mm2). The human carotid plaque surface (n = 2) displayed both well-organized and disrupted endothelium with similar features as described above. In addition, they were accompanied by extensive thrombotic areas. Conclusions: Our study unveils the spectrum of endothelial abnormalities associated with the development of atherosclerosis. These were highly abundant in early lesions and in the shoulder region of advanced plaques, while normalized at the advanced plaque's body. Similar endothelial features were observed in human atherosclerotic plaques, underlining the versatility of endothelial transformations in atherosclerosis.
KW - Atherosclerosis
KW - Endothelial junctions
KW - Endothelial permeability
KW - Endothelium
KW - Scanning electron microscopy
UR - http://www.scopus.com/inward/record.url?scp=85119987822&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.atherosclerosis.2021.11.017
DO - https://doi.org/10.1016/j.atherosclerosis.2021.11.017
M3 - Article
C2 - 34847419
SN - 0021-9150
VL - 339
SP - 35
EP - 45
JO - Atherosclerosis
JF - Atherosclerosis
ER -