TY - JOUR
T1 - Phenotypic transformation of intimal and adventitial lymphatics in atherosclerosis
T2 - A regulatory role for soluble VEGF receptor 2
AU - Taher, Mahdi
AU - Nakao, Shintaro
AU - Zandi, Souska
AU - Melhorn, Mark I.
AU - Hayes, K. C.
AU - Hafezi-Moghadam, Ali
N1 - Funding Information:
The authors thank the Malaysian Palm Oil Board. This work was supported by a DP3 IMPACT award from U.S. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Grant DK108238; a DiaComp award (to A.H.-M.); an overseas doctoral fellowship from the German Academic Exchange Service-DAAD (to M.T.); an overseas Research Fellowship Award from Bausch and Lomb; a fellowship award from the Japan Eye Bank Association; and a Tear Film and Ocular Surface Society Young Investigator Fellowship (to S.N.).
Publisher Copyright:
© FASEB.
PY - 2016/7
Y1 - 2016/7
N2 - 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 (apoE2/2 ) 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 apoE2/2 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 apoE2/2 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.
AB - 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 (apoE2/2 ) 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 apoE2/2 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 apoE2/2 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.
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U2 - 10.1096/fj.201500112
DO - 10.1096/fj.201500112
M3 - Article
C2 - 27006449
AN - SCOPUS:84978115917
VL - 30
SP - 2490
EP - 2499
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 7
ER -