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.
Highlights
The lymphatic vasculature collects and returns interstitial fluid to the blood
We recently described the stepwise morphogenesis of lymphovenous valves (LVVs) and reported that the PROX1high FOXC2high GATA2high LVV-forming ECs (LVV-ECs) are first observed at E12.0 (Geng et al 2016)
Ectopic expression of FOXC2 significantly rescues these defects. (K–N) Coimmunohistochemistry for the indicated markers revealed the presence of α-SMA+ mural cells on the VEGFR3+ lymphatic vessels of Lyve1-Cre;Cttnb1LOF embryos. (M) This defect is fully rescued by ectopic expression of
Summary
The lymphatic vasculature collects and returns interstitial fluid to the blood. The mammalian lymphatic vasculature is composed of lymphatic endothelial cells (LECs) that originate predominantly from embryonic veins, additional sources might exist (Srinivasan et al 2007; Martinez-Corral et al 2015; Stanczuk et al 2015). A subset of LEC progenitors stays on the veins to form four LVVs through the up-regulation of genes in addition to PROX1, such as FOXC2, GATA2, integrin α9 (ITGA9), and ITGA5 (Srinivasan and Oliver 2011; Geng et al 2016). A 50% reduction in the number of LVs is observed in Foxc2+/− embryos (Kanady et al 2015) Despite their critical roles, the mechanisms that control the expression of PROX1 and FOXC2, especially in the valves, have not yet been elucidated. The mesenteric lymphatic vessels do not undergo proper maturation, and LVs do not form in Clec2−/− mice with defective lymph flow (Sweet et al 2015). How OSS is sensed and translated into FOXC2 expression is not known
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