title: Sphingosine-1-Phosphate/Sphingosine-1-Phosphate Receptor 2 Axis Can Promote Mouse and Human Primary Mast Cell Angiogenic Potential through Upregulation of Vascular Endothelial Growth Factor-A and Matrix Metalloproteinase-2.
abstract: Mast cells (MC) are present in most vascularized tissues around the vasculature likely exerting immunomodulatory functions. Endowed with diverse mediators, resident MC represent first-line fine-tuners of local microenvironment. Sphingosine-1-phosphate (S1P) functions as a pluripotent signaling sphingolipid metabolite in health and disease. S1P formation occurs at low levels in resting MC and is upregulated upon activation. Its export can result in type 2 S1P receptor- (S1PR2-) mediated stimulation of MC, further fueling inflammation. However, the role of S1PR2 ligation in proangiogenic vascular endothelial growth factor- (VEGF-) A and matrix metalloproteinase- (MMP-) 2 release from MC is unknown. Using a preclinical MC-dependent model of acute allergic responses and in vitro stimulated primary mouse bone marrow-derived MC (BMMC) or human primary skin MC, we report that S1P signaling resulted in substantial amount of VEGF-A release. Similar experiments using S1pr2-deficient mice or BMMC or selective S1P receptor agonists or antagonists demonstrated that S1P/S1PR2 ligation on MC is important for VEGF-A secretion. Further, we show that S1P stimulation triggered transcriptional upregulation of VEGF-A and MMP-2 mRNA in human but not in mouse MC. S1P exposure also triggered MMP-2 secretion from human MC. These studies identify a novel proangiogenic axis encompassing MC/S1P/S1PR2 likely relevant to inflammation.
authors.affiliation: Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Building 2, Room C10, 6439 Garners Ferry Road, Columbia, SC 29209, USA.
authors.forename: Alena
authors.initials: A
authors.lastname: Chumanevich
authors.affiliation: Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Building 2, Room C10, 6439 Garners Ferry Road, Columbia, SC 29209, USA.
authors.forename: Piper
authors.initials: P
authors.lastname: Wedman
authors.affiliation: Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Building 2, Room C10, 6439 Garners Ferry Road, Columbia, SC 29209, USA.
authors.forename: Carole A
authors.initials: CA
authors.lastname: Oskeritzian
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; D000081025:Sphingosine-1-Phosphate Receptors; D042461:Vascular Endothelial Growth Factor A; C533955:sphingosine-1-phosphate receptor-2, mouse; C060506:sphingosine 1-phosphate; D020778:Matrix Metalloproteinase 2; D013110:Sphingosine