The Experts below are selected from a list of 51386922 Experts worldwide ranked by ideXlab platform
Timothy Hla - One of the best experts on this subject based on the ideXlab platform.
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endothelial sphingosine 1 phosphate receptors promote vascular normalization and antitumor therapy
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Andreane Cartier, Timothy Hla, Tani Leigh, Catherine H LiuAbstract:Sphingosine 1-phosphate receptor-1 (S1PR1) is essential for embryonic vascular development and maturation. In the adult, it is a key regulator of vascular barrier function and inflammatory processes. Its roles in tumor angiogenesis, tumor growth, and metastasis are not well understood. In this paper, we show that S1PR1 is expressed and active in tumor vessels. Murine tumor vessels that lack S1PR1 in the vascular endothelium (S1PR1 ECKO) show excessive vascular sprouting and branching, decreased barrier function, and poor perfusion accompanied by loose attachment of pericytes. Compound knockout of S1PR1, 2, and 3 genes further exacerbated these phenotypes, suggesting compensatory function of endothelial S1PR2 and 3 in the absence of S1PR1. On the other hand, tumor vessels with high expression of S1PR1 (S1PR1 ECTG) show less branching, tortuosity, and enhanced pericyte coverage. Larger tumors and enhanced lung metastasis were seen in S1PR1 ECKO, whereas S1PR1 ECTG showed smaller tumors and reduced metastasis. Furthermore, antitumor activity of a chemotherapeutic agent (doxorubicin) and immune checkpoint inhibitor blocker (anti-PD-1 antibody) were more effective in S1PR1 ECTG than in the wild-type counterparts. These data suggest that tumor endothelial S1PR1 induces vascular normalization and influences tumor growth and metastasis, thus enhancing antitumor therapies in mouse models. Strategies to enhance S1PR1 signaling in tumor vessels may be an important adjunct to standard cancer therapy of solid tumors.
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sphingosine 1 phosphate lipid signaling in pathology and therapy
Science, 2019Co-Authors: Andreane Cartier, Timothy HlaAbstract:Sphingosine 1-phosphate (S1P), a metabolic product of cell membrane sphingolipids, is bound to extracellular chaperones, is enriched in circulatory fluids, and binds to G protein-coupled S1P receptors (S1PRs) to regulate embryonic development, postnatal organ function, and disease. S1PRs regulate essential processes such as adaptive immune cell trafficking, vascular development, and homeostasis. Moreover, S1PR signaling is a driver of multiple diseases. The past decade has witnessed an exponential growth in this field, in part because of multidisciplinary research focused on this lipid mediator and the application of S1PR-targeted drugs in clinical medicine. This has revealed fundamental principles of lysophospholipid mediator signaling that not only clarify the complex and wide ranging actions of S1P but also guide the development of therapeutics and translational directions in immunological, cardiovascular, neurological, inflammatory, and fibrotic diseases.
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endothelial sphingosine 1 phosphate receptors promote vascular normalization to influence tumor growth and metastasis
bioRxiv, 2019Co-Authors: Andreane Cartier, Tani Leigh, Catherine H Liu, Timothy HlaAbstract:Abstract Sphingosine 1-phosphate receptor-1 (S1PR1) is essential for embryonic vascular development and maturation. In the adult, it is a key regulator of vascular barrier function and inflammatory processes. Its roles in tumor angiogenesis, tumor growth and metastasis are not well understood. In this report, we show that S1PR1 is expressed and active in tumor vessels. Tumor vessels that lack S1PR1 (S1PR1 ECKO) show excessive vascular sprouting and branching, decreased barrier function, and poor perfusion accompanied by loose attachment of pericytes. Compound knockout of S1PR1, 2 and 3 genes further exacerbated these phenotypes, suggesting compensatory function of endothelial S1PR2 and 3 in the absence of S1PR1. On the other hand, tumor vessels with high expression of S1PR1 (S1PR1 ECTG) show less branching, tortuosity and enhanced pericyte coverage. Larger tumors and enhanced lung metastasis were seen in S1PR1 ECKO whereas S1PR1 ECTG showed smaller tumors and reduced metastasis. Furthermore, anti-tumor activity of doxorubicin was more effective in S1PR1 ECTG than the wild-type counterparts. These data suggest that tumor endothelial S1PR1 induces vascular normalization and influences tumor growth, evolution and spread. Strategies to enhance S1PR1 signaling in tumor vessels may be an important adjunct to standard cancer therapy. Significance Endothelial sphingosine 1-phosphate receptors modulate tumor angiogenesis by inducing vascular normalization, which allows better blood circulation and enhanced anti-tumor therapeutic efficacy.
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S1PR1 sphingosine 1 phosphate receptor 1 signaling regulates blood flow and pressure
Hypertension, 2017Co-Authors: Anna Cantalupo, Timothy Hla, Catherine H Liu, Antonella Gargiulo, Elona Dautaj, Yi Zhang, Annarita Di LorenzoAbstract:Nitric oxide is one of the major endothelial-derived vasoactive factors that regulate blood pressure (BP), and the bioactive lipid mediator S1P (sphingosine-1-phosphate) is a potent activator of endothelial nitric oxide synthase through G protein-coupled receptors. Endothelial-derived S1P and the autocrine/paracrine activation of S1PR (S1P receptors) play an important role in preserving vascular functions and BP homeostasis. Furthermore, FTY720 (fingolimod), binding to 4 out of 5 S1PRs recently approved by the Food and Drug Administration to treat autoimmune conditions, induces a modest and transient decrease in heart rate in both animals and humans, suggesting that drugs targeting sphingolipid signaling affect cardiovascular functions in vivo. However, the role of specific S1P receptors in BP homeostasis remains unknown. The aim of this study is to determine the role of the key vascular S1P receptors, namely, S1PR1 and S1PR3, in BP regulation in physiological and hypertensive conditions. The specific loss of endothelial S1PR1 decreases basal and stimulated endothelial-derived nitric oxide and resets BP to a higher-than-normal value. Interestingly, we identified a novel and important role for S1PR1 signaling in flow-mediated mechanotransduction. FTY720, acting as functional antagonist of S1PR1, markedly decreases endothelial S1PR1, increases BP in control mice, and exacerbates hypertension in angiotensin II mouse model, underlining the antihypertensive functions of S1PR1 signaling. Our study identifies S1P-S1PR1-nitric oxide signaling as a new regulatory pathway in vivo of vascular relaxation to flow and BP homeostasis, providing a novel therapeutic target for the treatment of hypertension.
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individual variation of human s1p coding sequence leads to heterogeneity in receptor function and drug interactions
Journal of Lipid Research, 2014Co-Authors: Hideru Obinata, Sarah Gutkind, Jeremiah Stitham, Toshiaki Okuno, Takehiko Yokomizo, John Hwa, Timothy HlaAbstract:Sphingosine 1-phosphate receptor 1 (S1P1), an abundantly-expressed G protein-coupled receptor which regulates key vascular and immune responses, is a therapeutic target in autoimmune diseases. Fingolimod/Gilenya (FTY720), an oral medication for relapsing-remitting multiple sclerosis, targets S1P1 receptors on immune and neural cells to suppress neuroinflammation. However, suppression of endothelial S1P1 receptors is associated with cardiac and vascular adverse effects. Here we report the genetic variations of the S1P1 coding region from exon sequencing of >12,000 individuals and their functional consequences. We conducted functional analyses of 14 nonsynonymous single nucleotide polymorphisms (SNPs) of the S1PR1 gene. One SNP mutant (Arg120 to Pro) failed to transmit sphingosine 1-phosphate (S1P)-induced intracellular signals such as calcium increase and activation of p44/42 MAPK and Akt. Two other mutants (Ile45 to Thr and Gly305 to Cys) showed normal intracellular signals but impaired S1P-induced endocytosis, which made the receptor resistant to FTY720-induced degradation. Another SNP mutant (Arg13 to Gly) demonstrated protection from coronary artery disease in a high cardiovascular risk population. Individuals with this mutation showed a significantly lower percentage of multi-vessel coronary obstruction in a risk factor-matched case-control study. This study suggests that individual genetic variations of S1P1 can influence receptor function and, therefore, infer differential disease risks and interaction with S1P1-targeted therapeutics.
Catherine H Liu - One of the best experts on this subject based on the ideXlab platform.
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endothelial sphingosine 1 phosphate receptors promote vascular normalization and antitumor therapy
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Andreane Cartier, Timothy Hla, Tani Leigh, Catherine H LiuAbstract:Sphingosine 1-phosphate receptor-1 (S1PR1) is essential for embryonic vascular development and maturation. In the adult, it is a key regulator of vascular barrier function and inflammatory processes. Its roles in tumor angiogenesis, tumor growth, and metastasis are not well understood. In this paper, we show that S1PR1 is expressed and active in tumor vessels. Murine tumor vessels that lack S1PR1 in the vascular endothelium (S1PR1 ECKO) show excessive vascular sprouting and branching, decreased barrier function, and poor perfusion accompanied by loose attachment of pericytes. Compound knockout of S1PR1, 2, and 3 genes further exacerbated these phenotypes, suggesting compensatory function of endothelial S1PR2 and 3 in the absence of S1PR1. On the other hand, tumor vessels with high expression of S1PR1 (S1PR1 ECTG) show less branching, tortuosity, and enhanced pericyte coverage. Larger tumors and enhanced lung metastasis were seen in S1PR1 ECKO, whereas S1PR1 ECTG showed smaller tumors and reduced metastasis. Furthermore, antitumor activity of a chemotherapeutic agent (doxorubicin) and immune checkpoint inhibitor blocker (anti-PD-1 antibody) were more effective in S1PR1 ECTG than in the wild-type counterparts. These data suggest that tumor endothelial S1PR1 induces vascular normalization and influences tumor growth and metastasis, thus enhancing antitumor therapies in mouse models. Strategies to enhance S1PR1 signaling in tumor vessels may be an important adjunct to standard cancer therapy of solid tumors.
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endothelial sphingosine 1 phosphate receptors promote vascular normalization to influence tumor growth and metastasis
bioRxiv, 2019Co-Authors: Andreane Cartier, Tani Leigh, Catherine H Liu, Timothy HlaAbstract:Abstract Sphingosine 1-phosphate receptor-1 (S1PR1) is essential for embryonic vascular development and maturation. In the adult, it is a key regulator of vascular barrier function and inflammatory processes. Its roles in tumor angiogenesis, tumor growth and metastasis are not well understood. In this report, we show that S1PR1 is expressed and active in tumor vessels. Tumor vessels that lack S1PR1 (S1PR1 ECKO) show excessive vascular sprouting and branching, decreased barrier function, and poor perfusion accompanied by loose attachment of pericytes. Compound knockout of S1PR1, 2 and 3 genes further exacerbated these phenotypes, suggesting compensatory function of endothelial S1PR2 and 3 in the absence of S1PR1. On the other hand, tumor vessels with high expression of S1PR1 (S1PR1 ECTG) show less branching, tortuosity and enhanced pericyte coverage. Larger tumors and enhanced lung metastasis were seen in S1PR1 ECKO whereas S1PR1 ECTG showed smaller tumors and reduced metastasis. Furthermore, anti-tumor activity of doxorubicin was more effective in S1PR1 ECTG than the wild-type counterparts. These data suggest that tumor endothelial S1PR1 induces vascular normalization and influences tumor growth, evolution and spread. Strategies to enhance S1PR1 signaling in tumor vessels may be an important adjunct to standard cancer therapy. Significance Endothelial sphingosine 1-phosphate receptors modulate tumor angiogenesis by inducing vascular normalization, which allows better blood circulation and enhanced anti-tumor therapeutic efficacy.
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S1PR1 sphingosine 1 phosphate receptor 1 signaling regulates blood flow and pressure
Hypertension, 2017Co-Authors: Anna Cantalupo, Timothy Hla, Catherine H Liu, Antonella Gargiulo, Elona Dautaj, Yi Zhang, Annarita Di LorenzoAbstract:Nitric oxide is one of the major endothelial-derived vasoactive factors that regulate blood pressure (BP), and the bioactive lipid mediator S1P (sphingosine-1-phosphate) is a potent activator of endothelial nitric oxide synthase through G protein-coupled receptors. Endothelial-derived S1P and the autocrine/paracrine activation of S1PR (S1P receptors) play an important role in preserving vascular functions and BP homeostasis. Furthermore, FTY720 (fingolimod), binding to 4 out of 5 S1PRs recently approved by the Food and Drug Administration to treat autoimmune conditions, induces a modest and transient decrease in heart rate in both animals and humans, suggesting that drugs targeting sphingolipid signaling affect cardiovascular functions in vivo. However, the role of specific S1P receptors in BP homeostasis remains unknown. The aim of this study is to determine the role of the key vascular S1P receptors, namely, S1PR1 and S1PR3, in BP regulation in physiological and hypertensive conditions. The specific loss of endothelial S1PR1 decreases basal and stimulated endothelial-derived nitric oxide and resets BP to a higher-than-normal value. Interestingly, we identified a novel and important role for S1PR1 signaling in flow-mediated mechanotransduction. FTY720, acting as functional antagonist of S1PR1, markedly decreases endothelial S1PR1, increases BP in control mice, and exacerbates hypertension in angiotensin II mouse model, underlining the antihypertensive functions of S1PR1 signaling. Our study identifies S1P-S1PR1-nitric oxide signaling as a new regulatory pathway in vivo of vascular relaxation to flow and BP homeostasis, providing a novel therapeutic target for the treatment of hypertension.
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size selective opening of the blood brain barrier by targeting endothelial sphingosine 1 phosphate receptor 1
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Catherine H Liu, Sylvain Galvani, Giuseppe Faraco, Keisuke Yanagida, Helen Smith, Nathalie Burg, Josef AnratherAbstract:The vasculature of the central nervous system (CNS) forms a selective barrier termed the blood-brain barrier (BBB). Disruption of the BBB may contribute to various CNS diseases. Conversely, the intact BBB restricts efficient penetration of CNS-targeted drugs. Here, we report the BBB-regulatory role of endothelial sphingosine 1-phosphate (S1P) receptor-1, a G protein-coupled receptor known to promote the barrier function in peripheral vessels. Endothelial-specific S1PR1 knockout mice (S1PR1iECKO ) showed BBB breach for small-molecular-mass fluorescence tracers ( 10 kDa). Chronic BBB leakiness was associated with cognitive impairment, as assessed by the novel object recognition test, but not signs of brain inflammation. Brain microvessels of S1PR1iECKO mice showed altered subcellular distribution of tight junctional proteins. Pharmacological inhibition of S1P1 function led to transient BBB breach. These data suggest that brain endothelial S1P1 maintain the BBB by regulating the proper localization of tight junction proteins and raise the possibility that endothelial S1P1 inhibition may be a strategy for transient BBB opening and delivery of small molecules into the CNS.
Michael J. Kluk - One of the best experts on this subject based on the ideXlab platform.
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evaluation of S1PR1 pstat3 s1pr2 foxp1 expression in aggressive mature b cell lymphomas
Journal of Hematopathology, 2019Co-Authors: Mustafa Alkawaaz, Teresa Sanchez, Michael J. KlukAbstract:Background Aggressive, mature B-cell lymphomas include Burkitt Lymphoma (BL), High Grade B Cell Lymphomas (HGBL) (eg, Double-Hit B cell lymphomas (HGBL-DH: HGBL with MYC and BCL2 and/or BCL6 translocations)), HGBL, Not Otherwise Specified (HGBL, NOS) and Diffuse Large B Cell Lymphoma (DLBCL). Overlapping morphologic and immunohistochemical features of these lymphomas pose diagnostic challenges in some cases, and better understanding of potential diagnostic biomarkers and possible therapeutic targets is needed. Sphingosine 1 Phosphate Receptors (S1PR1-5) are G-protein coupled receptors that bind S1P and influence migration and survival in multiple cell types, including lymphocytes. S1PRs are emerging as biomarkers in B cell biology and interaction between S1PR pathways and STAT3 or FOXP1 has been reported in DLBCL. Aim and Methods Our aim was to extend the understanding of S1PR1, STAT3 and S1PR2, FOXP1 expression beyond DLBCL, into additional aggressive, mature B cell lymphomas using immunohistochemical expression analysis of human tissue samples. Results S1PR1 and S1PR2 showed different expression patterns in mantle zones and follicle centers in reactive lymphoid tissue. BL showed a unique expression pattern compared to HGBL and DLBCL. Additionally, S1PR1 and S1PR2 expression were typically mutually exclusive and were expressed in a low proportion of cases (frequently HGBL involving extranodal sites). FOXP1 was expressed in a high proportion of various case types and pSTAT3 was detected in a significant proportion of HGBL and DLBCL. Conclusions These findings provide further evidence that S1PR1, pSTAT3, S1PR2 and FOXP1 play a role in a subset of aggressive, mature B cell lymphomas.
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evaluation of S1PR1 pstat3 s1pr2 foxp1 expression in aggressive mature b cell lymphomas
Journal of Hematopathology, 2019Co-Authors: Mustafa Alkawaaz, Teresa Sanchez, Michael J. KlukAbstract:Aggressive, mature B cell lymphomas include Burkitt lymphoma (BL); high-grade B cell lymphomas (HGBL) (e.g., double-hit B cell lymphomas (HGBL-DH: HGBL with MYC and BCL2 and/or BCL6 translocations)); HGBL, not otherwise specified (HGBL, NOS); and diffuse large B cell lymphoma (DLBCL). Overlapping morphologic and immunohistochemical features of these lymphomas pose diagnostic challenges in some cases, and better understanding of potential diagnostic biomarkers and possible therapeutic targets is needed. Sphingosine 1 phosphate receptors (S1PR1-5) are G protein-coupled receptors that bind S1P and influence migration and survival in multiple cell types, including lymphocytes. S1PRs are emerging as biomarkers in B cell biology and interaction between S1PR pathways and STAT3 or FOXP1 has been reported in DLBCL. Our aim was to extend the understanding of S1PR1, STAT3, and S1PR2, FOXP1 expression beyond DLBCL, into additional aggressive, mature B cell lymphomas using immunohistochemical expression analysis of human tissue samples. S1PR1 and S1PR2 showed different expression patterns in mantle zones and follicle centers in reactive lymphoid tissue. BL showed a unique expression pattern compared to HGBL and DLBCL. Additionally, S1PR1 and S1PR2 expression were typically mutually exclusive and were expressed in a low proportion of cases (frequently HGBL involving extranodal sites). FOXP1 was expressed in a high proportion of various case types and pSTAT3 was detected in a significant proportion of HGBL and DLBCL. These findings provide further evidence that S1PR1, pSTAT3, S1PR2, and FOXP1 play a role in a subset of aggressive, mature B cell lymphomas.
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evaluation of S1PR1 pstat3 and s1pr2 foxp1 expression in aggressive mature b cell lymphomas
bioRxiv, 2018Co-Authors: Mustafa Alkawaaz, Teresa Sanchez, Michael J. KlukAbstract:Aggressive, mature B-cell lymphomas represent a heterogeneous group of diseases including Burkitt Lymphoma (BL), High Grade B Cell Lymphomas (HGBL) (eg, Double-Hit B cell lymphomas (HGBL-DH: HGBL with MYC and BCL2 and/or BCL6 translocations)), HGBL, Not Otherwise Specified (HGBL, NOS) and Diffuse Large B Cell Lymphoma. The overlapping morphologic and immunohistochemical features of these lymphomas may pose diagnostic challenges in some cases, and a better understanding of potential diagnostic biomarkers and possible therapeutic targets is needed. Sphingosine 1 Phosphate Receptors (S1PR1-5) represent a family of G-protein coupled receptors that bind the sphingolipid (S1P) and influence migration and survival pathways in a variety of cell types, including lymphocytes. S1PRs are emerging as biomarkers in B cell biology and interaction between S1PR pathways and STAT3 or FOXP1 has been reported, especially in DLBCL. Our aim was to extend the understanding of the S1PR1, STAT3 and S1PR2, FOXP1 expression beyond DLBCL, into additional aggressive, mature B cell lymphomas such as BL, HGBL-DH and HGBL,NOS. Herein, we report that S1PR1 and S1PR2 showed different patterns of expression in mantle zones and follicle centers in reactive lymphoid tissue and, among the lymphomas in this study, Burkitt lymphomas showed a unique pattern of expression compared to HGBL and DLBCL. Additionally, we found that S1PR1 and S1PR2 expression was typically mutually exclusive and were expressed in a low proportion of cases (predominantly HGBL involving extranodal sites). Lastly, FOXP1 was expressed in a high proportion of the various case types and pSTAT3 was detected in a significant proportion of HGBL and DLBCL cases. Taken together, these findings provide further evidence that S1PR1, pSTAT3, S1PR2 and FOXP1 play a role in a subset of aggressive mature B cell lymphomas.
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Lymphoma: Assessment of Expression and Role in Cell Migration
2016Co-Authors: Michael J. Kluk, Kieran Ryan, Guoqi Zhang, Bonnie Wang, Scott J. RodigAbstract:Classical Hodgkin lymphoma (CHL), a neoplasm of abnormal B lymphocytes (Hodgkin-Reed Sternberg cells), has been described to have a typical pattern of clinical presentation and dissemination often involving functionally contiguous lymph nodes. Despite the progress made in understanding CHL pathophysiology, the factors which regulate the spread of lymphoma cells in CHL are poorly understood. Sphingosine-1-Phosphate (S1P), a bioactive sphingolipid present at high concentrations in plasma and lymphatic fluid, is known to play a critical role in regulating lymphocyte trafficking mainly through S1PR1. In this study, we explore the role of the S1P-S1PR1 axis in Hodgkin lymphoma cell migration and the expression of S1PR1 in CHL cell lines and clinical cases. We found that S1PR1 is present in the KM-H2 and SUP-HD1 Hodgkin lymphoma cell lines at the mRNA and protein level. In addition, functionally, S1P potently stimulated migration of both cell lines. S1P-induced migration was inhibited by the S1PR1 antagonist, VPC44116 and the S1PR1 functional antagonist, FTY720-P, but was potentiated by the S1PR2 specific antagonist, JTE013. We also determined that S1PR1 induced migration in the KM-H2 and SUP-HD1 cells via the heterotrimeric G protein Gi and the phosphatidylinositol-3
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critical role of sphingosine 1 phosphate receptor 2 s1pr2 in acute vascular inflammation
Blood, 2013Co-Authors: Guoqi Zhang, Michael J. Kluk, Kieran Ryan, Rebekah K Odonnell, Katherine Spokes, William C Aird, Shulin Lü, Nathan I Shapiro, Li Yang, Kiichiro YanoAbstract:The endothelium, as the interface between blood and all tissues, plays a critical role in inflammation. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid, highly abundant in plasma, that potently regulates endothelial responses through interaction with its receptors (S1PRs). Here, we studied the role of S1PR2 in the regulation of the proadhesion and proinflammatory phenotype of the endothelium. By using genetic approaches and a S1PR2-specific antagonist (JTE013), we found that S1PR2 plays a key role in the permeability and inflammatory responses of the vascular endothelium during endotoxemia. Experiments with bone marrow chimeras (S1pr2+/+ → S1pr2+/+, S1pr2+/+ → S1pr2−/−, and S1pr2−/− → S1pr2+/+) indicate the critical role of S1PR2 in the stromal compartment, in the regulation of vascular permeability and vascular inflammation. In vitro, JTE013 potently inhibited tumor necrosis factor α–induced endothelial inflammation. Finally, we provide detailed mechanisms on the downstream signaling of S1PR2 in vascular inflammation that include the activation of the stress-activated protein kinase pathway that, together with the Rho-kinase nuclear factor kappa B pathway (NF-kB), are required for S1PR2-mediated endothelial inflammatory responses. Taken together, our data indicate that S1PR2 is a key regulator of the proinflammatory phenotype of the endothelium and identify S1PR2 as a novel therapeutic target for vascular disorders.
Keisuke Yanagida - One of the best experts on this subject based on the ideXlab platform.
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size selective opening of the blood brain barrier by targeting endothelial sphingosine 1 phosphate receptor 1
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Catherine H Liu, Sylvain Galvani, Giuseppe Faraco, Keisuke Yanagida, Helen Smith, Nathalie Burg, Josef AnratherAbstract:The vasculature of the central nervous system (CNS) forms a selective barrier termed the blood-brain barrier (BBB). Disruption of the BBB may contribute to various CNS diseases. Conversely, the intact BBB restricts efficient penetration of CNS-targeted drugs. Here, we report the BBB-regulatory role of endothelial sphingosine 1-phosphate (S1P) receptor-1, a G protein-coupled receptor known to promote the barrier function in peripheral vessels. Endothelial-specific S1PR1 knockout mice (S1PR1iECKO ) showed BBB breach for small-molecular-mass fluorescence tracers ( 10 kDa). Chronic BBB leakiness was associated with cognitive impairment, as assessed by the novel object recognition test, but not signs of brain inflammation. Brain microvessels of S1PR1iECKO mice showed altered subcellular distribution of tight junctional proteins. Pharmacological inhibition of S1P1 function led to transient BBB breach. These data suggest that brain endothelial S1P1 maintain the BBB by regulating the proper localization of tight junction proteins and raise the possibility that endothelial S1P1 inhibition may be a strategy for transient BBB opening and delivery of small molecules into the CNS.
Andreane Cartier - One of the best experts on this subject based on the ideXlab platform.
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endothelial sphingosine 1 phosphate receptors promote vascular normalization and antitumor therapy
Proceedings of the National Academy of Sciences of the United States of America, 2020Co-Authors: Andreane Cartier, Timothy Hla, Tani Leigh, Catherine H LiuAbstract:Sphingosine 1-phosphate receptor-1 (S1PR1) is essential for embryonic vascular development and maturation. In the adult, it is a key regulator of vascular barrier function and inflammatory processes. Its roles in tumor angiogenesis, tumor growth, and metastasis are not well understood. In this paper, we show that S1PR1 is expressed and active in tumor vessels. Murine tumor vessels that lack S1PR1 in the vascular endothelium (S1PR1 ECKO) show excessive vascular sprouting and branching, decreased barrier function, and poor perfusion accompanied by loose attachment of pericytes. Compound knockout of S1PR1, 2, and 3 genes further exacerbated these phenotypes, suggesting compensatory function of endothelial S1PR2 and 3 in the absence of S1PR1. On the other hand, tumor vessels with high expression of S1PR1 (S1PR1 ECTG) show less branching, tortuosity, and enhanced pericyte coverage. Larger tumors and enhanced lung metastasis were seen in S1PR1 ECKO, whereas S1PR1 ECTG showed smaller tumors and reduced metastasis. Furthermore, antitumor activity of a chemotherapeutic agent (doxorubicin) and immune checkpoint inhibitor blocker (anti-PD-1 antibody) were more effective in S1PR1 ECTG than in the wild-type counterparts. These data suggest that tumor endothelial S1PR1 induces vascular normalization and influences tumor growth and metastasis, thus enhancing antitumor therapies in mouse models. Strategies to enhance S1PR1 signaling in tumor vessels may be an important adjunct to standard cancer therapy of solid tumors.
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sphingosine 1 phosphate lipid signaling in pathology and therapy
Science, 2019Co-Authors: Andreane Cartier, Timothy HlaAbstract:Sphingosine 1-phosphate (S1P), a metabolic product of cell membrane sphingolipids, is bound to extracellular chaperones, is enriched in circulatory fluids, and binds to G protein-coupled S1P receptors (S1PRs) to regulate embryonic development, postnatal organ function, and disease. S1PRs regulate essential processes such as adaptive immune cell trafficking, vascular development, and homeostasis. Moreover, S1PR signaling is a driver of multiple diseases. The past decade has witnessed an exponential growth in this field, in part because of multidisciplinary research focused on this lipid mediator and the application of S1PR-targeted drugs in clinical medicine. This has revealed fundamental principles of lysophospholipid mediator signaling that not only clarify the complex and wide ranging actions of S1P but also guide the development of therapeutics and translational directions in immunological, cardiovascular, neurological, inflammatory, and fibrotic diseases.
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endothelial sphingosine 1 phosphate receptors promote vascular normalization to influence tumor growth and metastasis
bioRxiv, 2019Co-Authors: Andreane Cartier, Tani Leigh, Catherine H Liu, Timothy HlaAbstract:Abstract Sphingosine 1-phosphate receptor-1 (S1PR1) is essential for embryonic vascular development and maturation. In the adult, it is a key regulator of vascular barrier function and inflammatory processes. Its roles in tumor angiogenesis, tumor growth and metastasis are not well understood. In this report, we show that S1PR1 is expressed and active in tumor vessels. Tumor vessels that lack S1PR1 (S1PR1 ECKO) show excessive vascular sprouting and branching, decreased barrier function, and poor perfusion accompanied by loose attachment of pericytes. Compound knockout of S1PR1, 2 and 3 genes further exacerbated these phenotypes, suggesting compensatory function of endothelial S1PR2 and 3 in the absence of S1PR1. On the other hand, tumor vessels with high expression of S1PR1 (S1PR1 ECTG) show less branching, tortuosity and enhanced pericyte coverage. Larger tumors and enhanced lung metastasis were seen in S1PR1 ECKO whereas S1PR1 ECTG showed smaller tumors and reduced metastasis. Furthermore, anti-tumor activity of doxorubicin was more effective in S1PR1 ECTG than the wild-type counterparts. These data suggest that tumor endothelial S1PR1 induces vascular normalization and influences tumor growth, evolution and spread. Strategies to enhance S1PR1 signaling in tumor vessels may be an important adjunct to standard cancer therapy. Significance Endothelial sphingosine 1-phosphate receptors modulate tumor angiogenesis by inducing vascular normalization, which allows better blood circulation and enhanced anti-tumor therapeutic efficacy.
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cd4 t cell sphingosine 1 phosphate receptor s1pr 1 and s1pr4 and endothelial s1pr2 regulate afferent lymphatic migration
Science immunology, 2019Co-Authors: Yanbao Xiong, Ana Olivera, Wenji Piao, Colin C Brinkman, Lushen Li, Joseph M Kulinski, Andreane Cartier, Keli L Hippen, Bruce R. BlazarAbstract:Sphingosine 1-phosphate (S1P) and S1P receptors (S1PRs) regulate migration of lymphocytes out of thymus to blood and lymph nodes (LNs) to efferent lymph, whereas their role in other tissue sites is not known. Here, we investigated the question of how these molecules regulate leukocyte migration from tissues through afferent lymphatics to draining LNs (dLNs). S1P, but not other chemokines, selectively enhanced human and murine CD4 T cell migration across lymphatic endothelial cells (LECs). T cell S1PR1 and S1PR4, and LEC S1PR2, were required for migration across LECs and into lymphatic vessels and dLNs. S1PR1 and S1PR4 differentially regulated T cell motility and vascular cell adhesion molecule–1 (VCAM-1) binding. S1PR2 regulated LEC layer structure, permeability, and expression of the junction molecules VE-cadherin, occludin, and zonulin-1 through the ERK pathway. S1PR2 facilitated T cell transcellular migration through VCAM-1 expression and recruitment of T cells to LEC migration sites. These results demonstrated distinct roles for S1PRs in comodulating T cell and LEC functions in migration and suggest previously unknown levels of regulation of leukocytes and endothelial cells during homeostasis and immunity.
