Mechanotransduction activates canonical Wnt/β-catenin signaling to promote lymphatic vascular patterning and the development of lymphatic and lymphovenous valves.
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.
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA;
Boksik
B
Cha
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA;
Xin
X
Geng
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;
Md Riaj
MR
Mahamud
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA;
Jianxin
J
Fu
Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, USA;
Anish
A
Mukherjee
Department of Biological Sciences, Center for Systems Biology, The University of Texas at Dallas, Richardson, Texas 75080, USA;
Yeunhee
Y
Kim
Department of Life Science, University of Seoul, Seoul 130-743, Korea;
Eek-Hoon
EH
Jho
Department of Biological Sciences, Center for Systems Biology, The University of Texas at Dallas, Richardson, Texas 75080, USA;
Tae Hoon
TH
Kim
Department of Medicine, Division of Cardiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
Mark L
ML
Kahn
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;
Lijun
L
Xia
Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia 30332, USA;
J Brandon
JB
Dixon
Vascular Biology Program, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
Hong
H
Chen
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;
R Sathish
RS
Srinivasan
D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D006801:Humans; D042583:Lymphangiogenesis / Q000502:physiology*; D042601:Lymphatic Vessels / Q000196:embryology; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D051858:Forkhead Transcription Factors; D051176:beta Catenin; C082078:mesenchyme fork head 1 protein
FOXC2; PROX1; Wnt/β-catenin signaling; lymphatic valves; lymphatic vascular development; lymphovenous valves