Teresa Sanchez, PhD
Assistant Professor of Surgery
Beth Israel Deaconess Medical Center
Harvard Medical School
330 Brookline Avenue, RN-227A
Boston, MA 02215
Teresa Sanchez earned a PhD in Pharmacology and Cell Biology from the University of Barcelona (Spain) in 2001. Then, she did her post-doctoral training with Dr. Timothy Hla at the University of Connecticut School of Medicine, where she obtained a faculty position in 2005. Dr. Sanchez just joined the Department of Surgery at Beth Israel Deaconess Medical Center and became a member of the Center for Vascular Biology Research in July 2008.
Sphingolipid Signaling in Endothelial Injury
My laboratory investigates the signaling pathways which regulate the responses of the vascular endothelium to injury. More specifically, we are focused on the signaling pathways activated by sphingosine-1-phosphate (S1P). S1P, a bioactive sphingolipid present at high levels in plasma and lymph, regulates multiple cellular responses, by activating the endothelial differentiation gene family of G protein-coupled receptors (EDG-1-5, renamed S1P1-5R).
In order to better understand the role of S1P in the regulation of endothelial cell function, we have established several in vitro and in vivo systems. Using pharmacological modulators of S1P receptors and genetic models, we have shown that S1P is a critical modulator of endothelial cell migration and endothelial barrier function in vitro, as well as angiogenesis, vascular permeability and vascular inflammation in vivo. Interestingly, we found that vascular responses to S1P depend on the balance of expression of two of its receptors, S1P1R and S1P2R. Indeed, while activation of S1P1R inhibits vascular permeability and inflammation, activation of S1P2R promotes vascular permeability and endothelial inflammation. In addition, our studies have revealed the molecular mechanisms underlying the antagonistic effects of S1P1R and S1P2R in the regulation of endothelial responses. While S1P1R activates phosphatidylinositol-3-kinase (PI3K), S1P2R counteracts the actions of S1P1R by activating the phosphatase PTEN, which antagonizes the actions of PI3K. In agreement with this model, we found that PTEN activity was required for the inhibition of endothelial cell migration and induction of endothelial permeability by S1P2R.
Our findings emphasize the importance of understanding how S1P signaling is regulated in the endothelium. Since S1P receptors can be pharmacologically targeted by specific agonists and antagonists, understanding how S1P signaling is regulated both in health and disease will be important in the design of new therapies to treat disorders of vascular permeability, inflammation and vascular growth. We are presently using molecular and cell biology approaches in combination with animal models in order to further elucidate the signaling pathways activated by S1P receptors in several pathophysiological conditions.
New and Noteworthy Publications
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Sanchez T, Estrada-Hernandez T, Paik J-H, Wu M-T, Venkataraman K, Brinkmann V, Claffey KP, Hla T. Phosphorylation and action of the immunomodulator FTY720 inhibits VEGF-induced vascular permeability. J. Biol. Chem. 2003; 278:47281-47290.
This study was the first to demonstrate the inhibition of vascular endothelial growth factor (VEGF)-induced vascular permeability by pharmacological modulation of S1P receptors.
Sanchez T, Thangada S, Wu MT, Kontos CD, Wu D, Wu H, Hla T. PTEN as an effector in the signaling of antimigratory G protein-coupled receptor. Proc. Natl. Acad. Sci. U. S. A. 2005; 102(12):4312-4317.
This work gave insight into the molecular mechanisms responsible for the opposite effects of S1P1R and S1P2R on cell migration.
LaMontagne K, Littlewood-Evans A, Schnell C, O'Reilly T, Wyder L,
Sanchez T, Probst B, Butler J, Wood A, Liau G, Hla T, Wood J. The immunomodulator FTY720 inhibits angiogenesis and tumor vascularization. Cancer Res. 2006; 66:221-231.
This study showed the ability of FTY720, a pharmacological modulator of S1P receptors, to inhibit angiogenesis, vascular permeability and tumor growth in vivo.
Sanchez T, Skoura A, Wu M, Casserly B, Harrington EO, Hla T. Induction of vascular permeability by the sphingosine-1-phosphate receptor-2 (S1P2R). Arterioscler. Thromb. Vasc. Biol. 2007; 27(6): 1312-1318.
This was the first study to show the induction of vascular permeability by S1P2R and the molecular mechanisms involved.
Sanchez T, Claffey K, Mandala S, Proia R, Hla T. Essential role of sphingosine 1-phosphate receptor-2 in pathological angiogenesis of the mouse retina. J. Clin. Invest. 2007; 117(9): 2506-2516.
This report demonstrated the critical role of S1P2R in vascular permeability and endothelial inflammation using a murine model of retinopathy of prematurity.