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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL114820-01A1
Application #
8506262
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Tolunay, Eser
Project Start
2013-06-01
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$446,159
Indirect Cost
$177,994
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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
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
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