title: Phenotypic transformation of intimal and adventitial lymphatics in atherosclerosis: a regulatory role for soluble VEGF receptor 2.
abstract: The role of lymphatics in atherosclerosis is not yet understood. Here, we investigate lymphatic growth dynamics and marker expression in atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice. The prolymphangiogenic growth factor, VEGF-C, was elevated in atherosclerotic aortic walls. Despite increased VEGF-C, we found that adventitial lymphatics regress during the course of formation of atherosclerosis (P < 0.01). Similar to lymphatic regression, the number of lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1(+)) macrophages decreased in the aortic adventitia of apoE(-/-) mice with atherosclerosis (P < 0.01). Intimal lymphatics in the atherosclerotic lesions exhibited an atypical phenotype, with the expression of podoplanin and VEGF receptor 3 (VEGFR-3) but not of LYVE-1 and prospero homeobox protein 1. In the aortas of atherosclerotic animals, we found markedly increased soluble VEGFR-2. We hypothesized that the elevated soluble VEGFR-2 that was found in the aortas of apoE(-/-) mice with atherosclerosis binds to and diminishes the activity of VEGF-C. This trapping mechanism explains, despite increased VEGF-C in the atherosclerotic aortas, how adventitial lymphatics regress. Lymphatic regression impedes the drainage of lipids, growth factors, inflammatory cytokines, and immune cells. Insufficient lymphatic drainage could thus exacerbate atherosclerosis formation. Our study contributes new insights to previously unknown dynamic changes of adventitial lymphatics. Targeting soluble VEGFR-2 in atherosclerosis may provide a new strategy for the liberation of endogenous VEGF-C and the prevention of lymphatic regression.-Taher, M., Nakao, S., Zandi, S., Melhorn, M. I., Hayes, K. C., Hafezi-Moghadam, A. Phenotypic transformation of intimal and adventitial lymphatics in atherosclerosis: a regulatory role for soluble VEGF receptor 2.
authors.affiliation: Center for Excellence in Functional and Molecular Imaging, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Radiology and Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA; Institute of Biochemistry, Charité University Medical Center, Berlin, Germany; and.
authors.forename: Mahdi
authors.initials: M
authors.lastname: Taher
authors.affiliation: Center for Excellence in Functional and Molecular Imaging, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Radiology and Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA;
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nakao
authors.affiliation: Center for Excellence in Functional and Molecular Imaging, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Radiology and Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA;
authors.forename: Souska
authors.initials: S
authors.lastname: Zandi
authors.affiliation: Center for Excellence in Functional and Molecular Imaging, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Radiology and Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA;
authors.forename: Mark I
authors.initials: MI
authors.lastname: Melhorn
authors.affiliation: Department of Biology, Brandeis University, Waltham, Massachusetts, USA.
authors.forename: K C
authors.initials: KC
authors.lastname: Hayes
authors.affiliation: Center for Excellence in Functional and Molecular Imaging, Brigham and Women's Hospital, Boston, Massachusetts, USA; Department of Radiology and Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA; ahm@bwh.harvard.edu.
authors.forename: Ali
authors.initials: A
authors.lastname: Hafezi-Moghadam
mesh_terms: D063194:Adventitia; D000375:Aging; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000473:pathology*; D024142:Collagen Type VI; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D042583:Lymphangiogenesis; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins; D018345:Mice, Knockout; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*; D000098853:Podoplanin
chemical_list: D001057:Apolipoproteins E; D024142:Collagen Type VI; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2; C490441:Pdpn protein, mouse; D000098853:Podoplanin; C492273:LYVE1 protein, mouse; C000592875:Kdr protein, mouse
keywords: LYVE-1; VEGF-C; lymphangiogenesis; macrophages; podoplanin