Not just fibrotic: endothelial-derived TGFβ maintains contractile function and lymphatic muscle phenotype during...

Cell-cell communication within the lymphatic vasculature during homeostasis is incompletely detailed. Although many discoveries highlight the pathological roles of transforming growth factor-beta (TGFβ) in chronic vascular inflammation and associated fibrosis, only a small amount is known surrounding the role of TGFβ-signaling in homeostatic lymphatic function. Here, we discovered that pharmacological blockade of TGFβ receptor 1 (TGFβR1) negatively impacts rat mesenteric lymphatic vessel pumping, significantly reducing vessel contractility and surrounding lymphatic muscle coverage. We have identified mesenteric lymphatic endothelial cells themselves as a source of endogenous vascular TGFβ and that TGFβ production is significantly increased in these cells via activation of a number of functional pattern recognition receptors they express. We show that a continuous supply of TGFβ is essential to maintain the contractile phenotype of neighboring lymphatic muscle cells and support this conclusion through in vitro analysis of primary isolated lymphatic muscle cells that undergo synthetic differentiation during 2-D cell culture, a phenomenon that could be effectively rescued by supplementation with recombinant TGFβ. Finally, we demonstrate that lymphatic endothelial production of TGFβ is regulated, in part, by nitric oxide in a manner we propose is essential to counteract the pathological over-production of TGFβ. Taken together, these data highlight the essential role of homeostatic TGFβ signaling in the maintenance of lymphatic vascular function and highlight possible deleterious consequences of its inhibition.NEW & NOTEWORTHY The growth factor TGFβ is commonly associated with its pathological overproduction during tissue fibrosis rather than its homeostatic functions. We expose the lymphatic endothelium as a source of endogenous TGFβ, the impact of its production on the maintenance of surrounding lymphatic muscle cell phenotype, and internally regulated mechanisms of its production. Overall, these results highlight the intricate balance of TGFβ-signaling as an essential component of maintaining lymphatic contractile function.