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.
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.
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DOI：
10.1155/2016/1503206
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发表时间：
2016
影响因子：
4.6
通讯作者：
Oskeritzian CA
中科院分区：
文献类型：
--
作者：
Chumanevich A;Wedman P;Oskeritzian CA
肥大细胞（MC）存在于脉管周围的大多数血管化组织中，可能发挥免疫调节功能。居民MC被赋予不同的调解员，代表了当地微环境的一线微型型。鞘氨醇1-磷酸盐（S1P）在健康和疾病中充当多能信号鞘脂代谢物。 S1P的形成发生在静息MC的低水平，并且在激活后被上调。它的输出可以导致2型S1P受体 - （S1PR2-）介导的MC刺激，从而进一步加剧炎症。但是，S1PR2连接在促血管生成血管内皮生长因子（VEGF-）A和基质金属蛋白酶 - （MMP-）2从MC中释放的作用是未知的。使用急性过敏反应的临床前MC依赖性模型和体外刺激的原代小鼠骨髓衍生的MC（BMMC）或人类原发性皮肤MC，我们报告说S1P信号传导导致大量VEGF-A释放。使用S1PR2缺陷型小鼠或BMMC或选择性S1P受体激动剂或拮抗剂的类似实验表明，MC上的S1P/S1PR2连接对于VEGF-A分泌很重要。此外，我们表明S1P刺激触发了人类中VEGF-A和MMP-2 mRNA的转录上调，但在小鼠MC中却没有。 S1P暴露还触发了人类MC的MMP-2分泌。这些研究确定了一个新型的促血管生成轴，其中包含MC/S1P/S1PR2可能与炎症有关。
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.