Role of Flow in Lymphatic Vessel Remodeling and Patterning

Fluid shear forces have established roles in blood vascular development and function, but whether such forces also play important roles in the low flow, low pressure lymphatic system is unknown. Testing the role of fluid forces in vivo has been difficult because mechanical or genetic perturbations that alter flow often have direct effects on endothelial cells and vessel growth. Here, we investigate the functional role of fluid shear force in lymphatic vessel development using mice deficient in the platelet‐specific receptor CLEC2, in which blood back‐fills the lymphatic network and blocks lymph flow. CLEC2‐deficient animals exhibit normal growth of the primary mesenteric lymphatic plexus, but fail to remodel this plexus into a hierarchical structure typical of collecting vessels and fail to form lymphatic valves. In vitro studies in which lymphatic endothelial cells were exposed to a specific lymphatic flow regimen reveal that low, reversing shear stress is sufficient to induce expression of genes required for lymphatic valve development. Shear stress studies and analysis of CLEC2‐deficient mesenteric lymphatics identify GATA2 as an upstream transcriptional regulator of this lymphatic valve genetic program. These studies provide in vivo evidence that fluid forces regulate vascular development even in the low flow lymphatic system.