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

Boksik Cha, Xin Geng, Md Riaj Mahamud, Jianxin Fu, Anish Mukherjee, Yeunhee Kim, Eek Hoon Jho, Tae Hoon Kim, Mark L. Kahn, Lijun Xia, J. Brandon Dixon, Hong Chen, R. Sathish Srinivasan

Research output: Contribution to journalArticlepeer-review

102 Scopus citations

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.

Original languageEnglish
Pages (from-to)1454-1469
Number of pages16
JournalGenes and Development
Volume30
Issue number12
DOIs
StatePublished - 15 Jun 2016

Keywords

  • FOXC2
  • Lymphatic valves
  • Lymphatic vascular development
  • Lymphovenous valves
  • PROX1
  • Wnt/β-catenin signaling

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