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      Mechanotransduction activates canonical Wnt/β-catenin signaling to promote lymphatic vascular patterning and the development of lymphatic and lymphovenous valves.

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          Abstract

          Lymphatic vasculature regulates fluid homeostasis by returning interstitial fluid to blood circulation. Lymphatic endothelial cells (LECs) are the building blocks of the entire lymphatic vasculature. LECs originate as a homogeneous population of cells predominantly from the embryonic veins and undergo stepwise morphogenesis to become the lymphatic capillaries, collecting vessels or valves. The molecular mechanisms underlying the morphogenesis of the lymphatic vasculature remain to be fully understood. Here we show that canonical Wnt/β-catenin signaling is necessary for lymphatic vascular morphogenesis. Lymphatic vascular-specific ablation of β-catenin in mice prevents the formation of lymphatic and lymphovenous valves. Additionally, lymphatic vessel patterning is defective in these mice, with abnormal recruitment of mural cells. We found that oscillatory shear stress (OSS), which promotes lymphatic vessel maturation, triggers Wnt/β-catenin signaling in LECs. In turn, Wnt/β-catenin signaling controls the expression of several molecules, including the lymphedema-associated transcription factor FOXC2. Importantly, FOXC2 completely rescues the lymphatic vessel patterning defects in mice lacking β-catenin. Thus, our work reveals that mechanical stimulation is a critical regulator of lymphatic vascular development via activation of Wnt/β-catenin signaling and, in turn, FOXC2.

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          Author and article information

          Journal
          Genes Dev.
          Genes & development
          Cold Spring Harbor Laboratory
          1549-5477
          0890-9369
          Jun 15 2016
          : 30
          : 12
          Affiliations
          [1 ] Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA;
          [2 ] Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA; Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA;
          [3 ] Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, USA;
          [4 ] Department of Biological Sciences, Center for Systems Biology, The University of Texas at Dallas, Richardson, Texas 75080, USA;
          [5 ] Department of Life Science, University of Seoul, Seoul 130-743, Korea;
          [6 ] Department of Medicine, Division of Cardiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
          [7 ] Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA; Department of Biochemistry, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA;
          [8 ] Vascular Biology Program, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
          Article
          gad.282400.116
          10.1101/gad.282400.116
          4926867
          27313318

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