Platelet and Erythrocyte Sources of S1P Are Redundant for Vascular Development and Homeostasis, but Both Rendered Essential After Plasma S1P Depletion in Anaphylactic Shock.
Platelet and Erythrocyte Sources of S1P Are Redundant for Vascular Development and Homeostasis, but Both Rendered Essential After Plasma S1P Depletion in Anaphylactic Shock.
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DOI：
10.1161/circresaha.116.308929
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发表时间：
2016-09-30
影响因子：
20.1
通讯作者：
Camerer E
中科院分区：
文献类型：
--
作者：
Gazit SL;Mariko B;Thérond P;Decouture B;Xiong Y;Couty L;Bonnin P;Baudrie V;Le Gall SM;Dizier B;Zoghdani N;Ransinan J;Hamilton JR;Gaussem P;Tharaux PL;Chun J;Coughlin SR;Bachelot-Loza C;Hla T;Ho-Tin-Noé B;Camerer E
鞘氨醇-1-磷酸(S1P)信号对血管发育和出生后血管动态平衡是必不可少的。支持这些过程的S1P来源的冗余程度仍不清楚。解决S1P源冗余在调节血管发育、完整性和音调方面的问题。靶向缺失Sphks(Sphks)1和2的基因可选择性地损害小鼠的血小板、红细胞、内皮和/或平滑肌细胞产生S1P。S1P缺乏可钝化洗涤后的血小板的聚集和扩散，并严重削弱其促进体外内皮细胞屏障功能的能力。然而，与最近的报道相反，血小板或任何其他来源的S1P都不是血管发育、血管完整性或止血/血栓形成所必需的。然而，在全身过敏反应期间，血浆S1P迅速而严重地耗尽，使得血小板和红细胞来源的S1P成为生存所必需的，只有在没有循环来源的情况下才能观察到来自血液内皮的贡献。有但没有S1P的小鼠对阿司匹林的恢复很敏感，这表明血小板激活和刺激-反应耦合是必要的。S1P2介导了S1P的大部分生存益处，而内皮细胞S1P1尽管对维持血管完整性很重要，但对于生存来说是必不可少的。因此，S1P缺乏加重了血管麻痹，认为S1P在循环休克恢复期间维持血管阻力方面起着至关重要的作用。虽然来源冗余确保了S1P在血管发育和完整性中的重要作用，但在过敏性休克期间血浆S1P的严重枯竭使红细胞和血小板S1P池为恢复所必需，并使高基础血浆S1P水平受到保护。
Sphingosine-1-phosphate (S1P) signaling is essential for vascular development and postnatal vascular homeostasis. The level of redundancy in S1P sources sustaining these processes remains unclear. To address S1P source redundancy in the regulation of vascular development, integrity and tone. S1P production was selectively impaired in mouse platelets, erythrocytes, endothelium, and/or smooth muscle cells by targeted deletion of genes encoding sphingosine kinases (Sphks) 1&2. S1P deficiency blunted aggregation and spreading of washed platelets and profoundly impaired their capacity to promote endothelial barrier function ex vivo. However, and in contrast to recent reports, neither platelets nor any other source of S1P was essential for vascular development, vascular integrity, or hemostasis/thrombosis. Yet rapid and profound depletion of plasma S1P during systemic anaphylaxis rendered both platelet- and erythrocyte-derived S1P essential for survival, with a contribution from blood endothelium observed only in the absence of circulating sources. Recovery was sensitive to aspirin in mice with but not without platelet S1P, suggesting that platelet activation and stimulus-response coupling is needed. S1P2 mediated most of the survival benefit of S1P, while endothelial S1P1 was dispensable for survival despite its importance for maintaining vascular integrity. Accordingly, S1P deficiency aggravated vasoplegia, arguing a vital role for S1P in maintaining vascular resistance during recovery from circulatory shock. While source redundancy secures essential roles of S1P in vascular development and integrity, profound depletion of plasma S1P during anaphylactic shock renders both erythrocyte and platelet S1P pools necessary for recovery and high basal plasma S1P levels protective.