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Lymph flow regulates collecting lymphatic vessel maturation in vivo
Daniel T. Sweet, … , Peter F. Davies, Mark L. Kahn
Daniel T. Sweet, … , Peter F. Davies, Mark L. Kahn
Published July 27, 2015
Citation Information: J Clin Invest. 2015;125(8):2995-3007. https://doi.org/10.1172/JCI79386.
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Research Article Angiogenesis Cardiology Development Oncology Vascular biology

Lymph flow regulates collecting lymphatic vessel maturation in vivo

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Abstract

Fluid shear forces have established roles in blood vascular development and function, but whether such forces similarly influence the low-flow lymphatic system is unknown. It has been difficult to test the contribution of fluid forces in vivo because mechanical or genetic perturbations that alter flow often have direct effects on vessel growth. Here, we investigated the functional role of flow in lymphatic vessel development using mice deficient for the platelet-specific receptor C-type lectin–like receptor 2 (CLEC2) as blood backfills the lymphatic network and blocks lymph flow in these animals. CLEC2-deficient animals exhibited normal growth of the primary mesenteric lymphatic plexus but failed to form valves in these vessels or remodel them into a structured, hierarchical network. Smooth muscle cell coverage (SMC coverage) of CLEC2-deficient lymphatic vessels was both premature and excessive, a phenotype identical to that observed with loss of the lymphatic endothelial transcription factor FOXC2. In vitro evaluation of lymphatic endothelial cells (LECs) revealed that low, reversing shear stress is sufficient to induce expression of genes required for lymphatic valve development and identified GATA2 as an upstream transcriptional regulator of FOXC2 and the lymphatic valve genetic program. These studies reveal that lymph flow initiates and regulates many of the key steps in collecting lymphatic vessel maturation and development.

Authors

Daniel T. Sweet, Juan M. Jiménez, Jeremy Chang, Paul R. Hess, Patricia Mericko-Ishizuka, Jianxin Fu, Lijun Xia, Peter F. Davies, Mark L. Kahn

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Figure 6

GATA2 is required for flow-induced expression of lymphatic valve genes.

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GATA2 is required for flow-induced expression of lymphatic valve genes....
(A and B) Changes in LEC valve gene expression induced by lymphatic fluid shear following siRNA knockdown of GATA2. Gene expression was measured following transfection with siGATA2 or control siRNA (siControl) in static LEC or LEC exposed to lymphatic flow for 24 hours. n = 4 independent experiments. All values are means ± SEM. **P < 0.01, ***P < 0.001, calculated by Student’s t test. (C) Western blot of FOXC2 molecular weight shift in siControl vs. siGATA2 LEC exposed to lymphatic shear for 24 hours or kept static. n = 3 experiments. (D–K) Whole-mount staining for FOXC2 (green), GATA2 (red), and PROX1-GFP (blue) in E17.5 mesenteric lymphatic vessels of Clec2+/+ and Clec2–/– embryos. Scale bars: 100 μm.
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