Author:
Cha Boksik,Geng Xin,Mahamud Md. Riaj,Fu Jianxin,Mukherjee Anish,Kim Yeunhee,Jho Eek-hoon,Kim Tae Hoon,Kahn Mark L.,Xia Lijun,Dixon J. Brandon,Chen Hong,Srinivasan R. Sathish
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.
Funder
National Institutes of Health
Oklahoma Medical Research Foundation
Oklahoma Center for Adult Stem Cell Research
American Heart Association
National Research Foundation
National Institute of Allergy and Infectious Diseases
Publisher
Cold Spring Harbor Laboratory
Subject
Developmental Biology,Genetics
Cited by
114 articles.
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