In this grant proposal we seek to characterize how BMPER, an extracellular regulator of the BMP signaling pathway, influences the biology and function of endothelial cells. Understanding the biology of endothelial cells and the signaling pathways they use in order to orchestrate their pleiotropy of function is of critical importance given the vast array of cardiovascular, circulatory and blood diseases that result from the dysfunction of the vascular endothelium. Work in our laboratory and others has revealed that BMPER, through it's mediation of BMP signaling events, is critically involved in numerous aspects of endothelial cell biology that impinge on and affect vascular development in the embryo and the success of revascularization in mature tissues. Defining the mechanism behind BMPER's ability to affect these processes, however, has been complicated due to the unusual ability of BMPER to both promote and inhibit BMP activity in a context-dependent manner. Recently, we have discovered that BMPER modulates BMP4 activity via a concentration-dependent, endocytic trap-and- sink mechanism, with low levels of BMPER promoting and high levels inhibiting BMP4 signaling, thereby accounting for the biphasic nature of BMPER's regulation of BMP4 activity. Furthermore, we found that the differential recruitment of receptor complex proteins, determined by the concentration ratio of BMPER to BMP4, predisposes the BMPER/BMP4 signaling complex to be sorted by intracellular compartments that result in either the enhancement or inhibition of BMP activation. Here we propose to build on these findings by using a novel and highly integrated approach in which vascular events at the molecular, transcriptional, and genetic level will be related to pathologically and therapeutically relevant processes within the endothelial compartment. Specifically, we propose to: 1). Understand the broad biochemical regulation of BMPER activity in endothelial cells;2). Elucidate the role of BMPER in the regulation of signaling events necessary for endothelial cell migration;and 3). Determine the role of BMPER-mediated signaling during coronary angiogenesis, a process that until now, has not been explored in terms of BMPER/BMP signaling but which our preliminary data demonstrate is reliant on BMPER.
The aims of this grant are a logical extension of work done in the previous cycle. We anticipate that this approach, while challenging in its scope, will allow the individual parts of the project to be synergistic without being interdependent on one another for completion, should problems arise in one area.
Understanding the biology of key components of the cardiovascular system, such as the endothelial cells we focus on in this proposal, is necessary and essential for both determining the causes of cardiovascular diseases and for developing safe and specific therapies. The BMPER/BMP signaling pathway has been implicated in embryonic development, adult vascular regeneration and in tumor biology. The results of the experiments outlined in this proposal have the potential to directly impact public health by identifying viable therapeutic options to treat a wide range of cardiovascular conditions.
|Mao, Hua; Lockyer, Pamela; Li, Luge et al. (2017) Endothelial LRP1 regulates metabolic responses by acting as a co-activator of PPAR?. Nat Commun 8:14960|
|Angelini, Aude; Pi, Xinchun; Xie, Liang (2017) Dioxygen and Metabolism; Dangerous Liaisons in Cardiac Function and Disease. Front Physiol 8:1044|
|Lockyer, Pamela; Mao, Hua; Fan, Qiying et al. (2017) LRP1-Dependent BMPER Signaling Regulates Lipopolysaccharide-Induced Vascular Inflammation. Arterioscler Thromb Vasc Biol 37:1524-1535|
|Mao, Hua; Lockyer, Pamela; Townley-Tilson, W H Davin et al. (2016) LRP1 Regulates Retinal Angiogenesis by Inhibiting PARP-1 Activity and Endothelial Cell Proliferation. Arterioscler Thromb Vasc Biol 36:350-60|
|Townley-Tilson, W H Davin; Pi, Xinchun; Xie, Liang (2015) The Role of Oxygen Sensors, Hydroxylases, and HIF in Cardiac Function and Disease. Oxid Med Cell Longev 2015:676893|
|Dyer, Laura; Lockyer, Pamela; Wu, Yaxu et al. (2015) BMPER Promotes Epithelial-Mesenchymal Transition in the Developing Cardiac Cushions. PLoS One 10:e0139209|
|Xie, Liang; Pi, Xinchun; Wang, Zhongjing et al. (2015) Depletion of PHD3 protects heart from ischemia/reperfusion injury by inhibiting cardiomyocyte apoptosis. J Mol Cell Cardiol 80:156-65|
|Xie, Liang; Pi, Xinchun; Townley-Tilson, W H Davin et al. (2015) PHD2/3-dependent hydroxylation tunes cardiac response to ?-adrenergic stress via phospholamban. J Clin Invest 125:2759-71|
|Dyer, Laura A; Pi, Xinchun; Patterson, Cam (2014) The role of BMPs in endothelial cell function and dysfunction. Trends Endocrinol Metab 25:472-80|
|Townley-Tilson, W H Davin; Wu, Yaxu; Ferguson 3rd, James E et al. (2014) The ubiquitin ligase ASB4 promotes trophoblast differentiation through the degradation of ID2. PLoS One 9:e89451|
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