title: Adventitial lymphatic capillary expansion impacts on plaque T cell accumulation in atherosclerosis.
abstract: During plaque progression, inflammatory cells progressively accumulate in the adventitia, paralleled by an increased presence of leaky vasa vasorum. We here show that next to vasa vasorum, also the adventitial lymphatic capillary bed is expanding during plaque development in humans and mouse models of atherosclerosis. Furthermore, we investigated the role of lymphatics in atherosclerosis progression. Dissection of plaque draining lymph node and lymphatic vessel in atherosclerotic ApoE-/-mice aggravated plaque formation, which was accompanied by increased intimal and adventitial CD3+T cell numbers. Likewise, inhibition of VEGF-C/D dependent lymphangiogenesis by AAV aided gene transfer of hVEGFR3-Ig fusion protein resulted in CD3+T cell enrichment in plaque intima and adventitia. hVEGFR3-Ig gene transfer did not compromise adventitial lymphatic density, pointing to VEGF-C/D independent lymphangiogenesis. We were able to identify the CXCL12/CXCR4 axis, which has previously been shown to indirectly activate VEGFR3, as a likely pathway, in that its focal silencing attenuated lymphangiogenesis and augmented T cell presence. Taken together, our study not only shows profound, partly CXCL12/CXCR4 mediated, expansion of lymph capillaries in the adventitia of atherosclerotic plaque in humans and mice, but also is the first to attribute an important role of lymphatics in plaque T cell accumulation and development.
authors.affiliation: Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands.
authors.forename: Timo
authors.initials: T
authors.lastname: Rademakers
authors.affiliation: Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands.|Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Emiel P C
authors.initials: EP
authors.lastname: van der Vorst
authors.affiliation: Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands.
authors.forename: Isabelle T M N
authors.initials: IT
authors.lastname: Daissormont
authors.affiliation: Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands.
authors.forename: Jeroen J T
authors.initials: JJ
authors.lastname: Otten
authors.affiliation: Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands.
authors.forename: Kosta
authors.initials: K
authors.lastname: Theodorou
authors.affiliation: Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Theelen
authors.affiliation: Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands.|Department of Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands.|Department of Medical Biochemistry, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Marion
authors.initials: M
authors.lastname: Gijbels
authors.affiliation: Wihuri Research Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Andrey
authors.initials: A
authors.lastname: Anisimov
authors.affiliation: Wihuri Research Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Harri
authors.initials: H
authors.lastname: Nurmi
authors.affiliation: Departments of Vascular Surgery and Transplantation Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jan H N
authors.initials: JH
authors.lastname: Lindeman
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schober
authors.affiliation: Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Heeneman
authors.affiliation: Wihuri Research Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.affiliation: Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, the Netherlands.|Institute for Molecular Cardiovascular Research, RWTH Aachen, Germany.
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
mesh_terms: D063194:Adventitia / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D054377:Chemokine CXCL12 / Q000378:metabolism; D006801:Humans; D042601:Lymphatic Vessels / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000473:pathology; D019718:Receptors, CXCR4 / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D042461:Vascular Endothelial Growth Factor A