Differential roles of BMP-SMAD1/5 signalling in lymphatic collecting vessels and capillaries

The lymphatic system drains interstitial tissue fluid back into the blood vascular system to maintain fluid homeostasis and prevent tissue swelling. A dysfunctional lymphatic vasculature is associated with development of lymphedema affecting worldwide more than 170 million people. Unfortunately, no real cure exists. Understanding the molecular mechanisms that regulate lymphatic vessel patterning and differentiation of organ-specific lymphatic beds can contribute to important new insights that may advance the design of diseasetailored therapies of lymphedema. In recent years, studies have highlighted the importance of the bone morphogenetic protein (BMP) signalling pathway in lymphatic vessel biology and disease. Using reporter mice, our lab has shown very selective spatio-temporal regions of BMP signalling output by SMAD effectors in different organ-specific lymphatic beds in developing mice. Moreover, in mice with lymphatic endothelium-specific inactivation of Smad1 and Smad5, we have shown that SMAD1/5 stabilizes the lymphangion, the vessel segment between two valve regions, by regulating the WNT signalling pathway. However, the lymphatic capillary defect and the role of SMAD1/5 in other lymphatic networks remain unexplored. We therefore aim to identify the organ-specific functions of the BMPSMAD1/5 signalling pathway in lymphatic endothelium using the mouse model and a recent in vitro RNA-Seq dataset, including a translation of these results in human samples.