期刊
GENES & DEVELOPMENT
卷 30, 期 12, 页码 1454-1469出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.282400.116
关键词
FOXC2; lymphatic valves; lymphatic vascular development; lymphovenous valves; PROX1; Wnt/beta-catenin signaling
资金
- National Institutes of Health/National Heart, Lung, and Blood Institute [R01HL131652]
- Oklahoma Medical Research Foundation
- Oklahoma Center for Adult Stem Cell Research (OCASCR) [4340]
- American Heart Association [15BGIA25710032, 15POST25080182]
- National Research Foundation - Ministry of Science, ICT, and Future Planning of the Republic of Korea [2012M3A9C6050109]
- National Institute of Allergy and Infectious Diseases [R21AI107067]
- National Cancer Institute [R01CA140485]
- National Research Foundation of Korea [2012M3A9C6050107] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- Directorate For Engineering
- Div Of Civil, Mechanical, & Manufact Inn [1351341] Funding Source: National Science Foundation
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/beta-catenin signaling is necessary for lymphatic vascular morphogenesis. Lymphatic vascular-specific ablation of beta-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/beta-catenin signaling in LECs. In turn, Wnt/beta-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 beta-catenin. Thus, our work reveals that mechanical stimulation is a critical regulator of lymphatic vascular development via activation of Wnt/beta-catenin signaling and, in turn, FOXC2.
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