The overall goal of this proposal is to explore novel ways of targeting endothelial cells to impact vascular functions in the pathogenesis of cardiovascular diseases, including heart failure. Despite a variety of evidences have linked the alteration of sphingolipid signaling to endothelial dysfunction, critical event in the development f cardiovascular pathologies, specific molecular mechanisms are poorly understood. Towards this goal, we will investigate how endothelial-derived sphingolipids are regulated and what are their roles on the vascular functions to impact the pathogenesis of heart failure (HF). These are fundamental problems that apply to all cardiovascular diseases, where the alteration of endothelial function is a critical event in the onset of these pathologies. The project will focus n our recent discovery that endothelial sphingolipid synthesis is negatively regulated by Nogo-B, a membrane protein of the endoplasmic reticulum. Our findings evidence a critical role of local endothelial sphingolipid production to regulate vascular barrier functions in myocardial inflammation and reveal a novel regulation of endothelial sphingolipid synthesis by Nogo-B. Thus, we hypothesize that Nogo-B governs the production of local sphingolipids to impact endothelial functions and heart failure during pressure overload. As corollary to this hypothesis, we predict that modulating sphingolipid synthesis will protect the heart from inflammation and failure. To test this hypothesis we are proposing the following three specific aims: 1) To define the molecular mechanisms whereby Nogo-B regulates sphingolipid de novo synthesis in EC. 2) To examine the role of endothelial specific Nogo-B on the pathogenesis of HF by conditional deletion of Nogo-B in EC. 3) To decipher the importance of S1P as a key effector of endothelial Nogo-B functions to impact HF, in mice lacking sphingosine kinase 1 and Nogo-B specifically in EC. Collectively, these studies will define a novel regulatory mechanism of endothelial sphingolipid synthesis by Nogo-B, and its importance in the pathogenesis of heart failure. Finally, the results of these proposed investigations may provide the foundation for novel approaches towards the treatment of heart failure, in which vascular dysfunction and inflammation leads to or exacerbates this pathological state. .

Public Health Relevance

The overall goal of this proposal is to explore novel ways of targeting endothelial cells to impact vascular functions in the pathogenesis of cardiovascular diseases, including heart failure, a growing public health problem for which the current pharmacological therapies aimed at the prevention are inadequate. This proposal will study the regulation of endothelial produced sphingolipids to impact myocardial vascular functions and heart failure. These proposed studies will contribute to understand the role and regulation of locally produced sphingolipids on endothelial cell functions and heart failure, and may lead to new pharmacological approaches for the treatment of cardiovascular diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Gao, Yunling
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Weill Medical College of Cornell University
Schools of Medicine
New York
United States
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Xu, Ren; Yallowitz, Alisha; Qin, An et al. (2018) Targeting skeletal endothelium to ameliorate bone loss. Nat Med 24:823-833
Swendeman, Steven L; Xiong, Yuquan; Cantalupo, Anna et al. (2017) An engineered S1P chaperone attenuates hypertension and ischemic injury. Sci Signal 10:
Cantalupo, Anna; Gargiulo, Antonella; Dautaj, Elona et al. (2017) S1PR1 (Sphingosine-1-Phosphate Receptor 1) Signaling Regulates Blood Flow and Pressure. Hypertension 70:426-434
Christensen, Pernille M; Liu, Catherine H; Swendeman, Steven L et al. (2016) Impaired endothelial barrier function in apolipoprotein M-deficient mice is dependent on sphingosine-1-phosphate receptor 1. FASEB J 30:2351-9
Sasset, Linda; Zhang, Yi; Dunn, Teresa M et al. (2016) Sphingolipid De Novo Biosynthesis: A Rheostat of Cardiovascular Homeostasis. Trends Endocrinol Metab 27:807-819
Zhang, Yi; Huang, Yan; Cantalupo, Anna et al. (2016) Endothelial Nogo-B regulates sphingolipid biosynthesis to promote pathological cardiac hypertrophy during chronic pressure overload. JCI Insight 1:
Cantalupo, Anna; Di Lorenzo, Annarita (2016) S1P Signaling and De Novo Biosynthesis in Blood Pressure Homeostasis. J Pharmacol Exp Ther 358:359-70
Cantalupo, Anna; Zhang, Yi; Kothiya, Milankumar et al. (2015) Nogo-B regulates endothelial sphingolipid homeostasis to control vascular function and blood pressure. Nat Med 21:1028-1037