Lymph flow regulates collecting lymphatic vessel maturation in vivo
DT Sweet, JM Jiménez, J Chang… - The Journal of …, 2015 - Am Soc Clin Investig
The Journal of clinical investigation, 2015•Am Soc Clin Investig
Fluid shear forces have established roles in blood vascular development and function, but
whether such forces similarly influence the low-flow lymphatic system is unknown. It has
been difficult to test the contribution of fluid forces in vivo because mechanical or genetic
perturbations that alter flow often have direct effects on vessel growth. Here, we investigated
the functional role of flow in lymphatic vessel development using mice deficient for the
platelet-specific receptor C-type lectin–like receptor 2 (CLEC2) as blood backfills the …
whether such forces similarly influence the low-flow lymphatic system is unknown. It has
been difficult to test the contribution of fluid forces in vivo because mechanical or genetic
perturbations that alter flow often have direct effects on vessel growth. Here, we investigated
the functional role of flow in lymphatic vessel development using mice deficient for the
platelet-specific receptor C-type lectin–like receptor 2 (CLEC2) as blood backfills the …
Fluid shear forces have established roles in blood vascular development and function, but whether such forces similarly influence the low-flow lymphatic system is unknown. It has been difficult to test the contribution of fluid forces in vivo because mechanical or genetic perturbations that alter flow often have direct effects on vessel growth. Here, we investigated the functional role of flow in lymphatic vessel development using mice deficient for the platelet-specific receptor C-type lectin–like receptor 2 (CLEC2) as blood backfills the lymphatic network and blocks lymph flow in these animals. CLEC2-deficient animals exhibited normal growth of the primary mesenteric lymphatic plexus but failed to form valves in these vessels or remodel them into a structured, hierarchical network. Smooth muscle cell coverage (SMC coverage) of CLEC2-deficient lymphatic vessels was both premature and excessive, a phenotype identical to that observed with loss of the lymphatic endothelial transcription factor FOXC2. In vitro evaluation of lymphatic endothelial cells (LECs) revealed that low, reversing shear stress is sufficient to induce expression of genes required for lymphatic valve development and identified GATA2 as an upstream transcriptional regulator of FOXC2 and the lymphatic valve genetic program. These studies reveal that lymph flow initiates and regulates many of the key steps in collecting lymphatic vessel maturation and development.
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