Lymphatic vessels are essential to maintain homeostasis of individuals. Although several factors that promote lymphatic development have been identified, those that negatively regulate lymphatic development remain currently unknown. We have recently demonstrated that Bone Morphogenetic Protein 2 (BMP2) signaling functions as a context dependent pro-angiogenic cue in zebrafish, promoting angiogenesis from venous endothelial cells without affecting arterial endothelial cells. Interestingly, BMP2 signalin exerts its pro-angiogenic effects on venous endothelial cells at the expense of lymphatic endothelial cells (LECs). In embryos with an elevated level of BMP2 signaling, lymphatic endothelial cells fail to emerge. BMP2 signaling appears to inhibit the onset of prox1 expression while promoting the expression of miR-181a and miR-31, both of which are known to negatively regulate prox1. Moreover, BMP2 signaling attenuates the cellular response to VEGF-C signaling in LECs, and functionally interacts with the main VEGF-C receptor, Vegfr3/Ftl4, therefore, is likely to attenuate Vegf-C signaling. Based on our preliminary data, we hypothesize that BMP signaling negatively regulates lymphatic development. To fully understand the molecular and cellular mechanisms that enable the function of BMP2 signaling, we propose two specific aims to investigate, using zebrafish and cell culture models. We will determine molecular and cellular mechanisms that mediate BMP function in LECs and investigate how BMP2 signaling impacts lymphatic development (Aim 1), and delineate how BMP2 signaling modulates subsequent lymphatic patterning (Aim 2). We will accomplish these goals using innovative approaches and models. We anticipate that the knowledge of how BMP2 effects lymphatic vessels gained through this work will be significant both in increasing our basic understanding of how lymphatic development is coordinated and provide a theoretical background in developing therapeutic interventions for lymphedema and other dysfunctions of lymphatic vessels.

Public Health Relevance

Lymphatic vessel provides essential functions to maintain homeostasis in all vertebrate animals, including humans, of which problems can lead to debilitating condition known as lymphedema. We have recently found Bone Morphogenetic Protein2 (BMP2) negatively regulates lymphatic vessel growth, making them the first signal that inhibits lymphatic vessel growth. We will investigate how BMP2 signaling regulates lymphatic vessels using multiple models to better understand the function of BMP2 signal to provide scientific background to develop new treatments for lymphedema patients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular Differentiation and Development Study Section (CDD)
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Tolunay, Eser
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Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
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Mouillesseaux, Kevin P; Wiley, David S; Saunders, Lauren M et al. (2016) Notch regulates BMP responsiveness and lateral branching in vessel networks via SMAD6. Nat Commun 7:13247
Kim, Jun-Dae; Lee, Heon-Woo; Jin, Suk-Won (2014) Diversity is in my veins: role of bone morphogenetic protein signaling during venous morphogenesis in zebrafish illustrates the heterogeneity within endothelial cells. Arterioscler Thromb Vasc Biol 34:1838-45
Kim, Jun-Dae; Kang, Yujung; Kim, Jongmin et al. (2014) Essential role of Apelin signaling during lymphatic development in zebrafish. Arterioscler Thromb Vasc Biol 34:338-45
Dunworth, William P; Cardona-Costa, Jose; Bozkulak, Esra Cagavi et al. (2014) Bone morphogenetic protein 2 signaling negatively modulates lymphatic development in vertebrate embryos. Circ Res 114:56-66