Platelet and Erythrocyte Sources of S1P Are Redundant for Vascular Development and Homeostasis, but Both Rendered Essential After Plasma S1P Depletion in Anaphylactic Shock

Abstract

Rationale 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. Objective To address S1P source redundancy in the regulation of vascular development, integrity and tone. Methods and Results 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. Conclusions 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.

Endotoxemia rocks sphingolipid metabolism at the blood–brain barrier

“…), genetic deficiency in the production of circulating but not endothelial S1P phenocopies lung leak observed in endothelial S1PR1‐deficient mice (Gazit et al . ). Endothelial‐selective S1PR1 deficiency also results in loss of BBB integrity, although the phenotype is more subtle and size selective (Yanagida et al .…”

“…; Gazit et al . ). Extending the characterization of cerebral sphingolipid metabolism to cardiogenic and anaphylactic shock and localized cerebral ischemia could help to further unravel mechanisms of S1P pathway deregulation, and evaluate if observations made in this study may be more broadly relevant to critical illness‐induced cognitive dysfunction (Pandharipande et al .…”

“…In a mouse model of anaphylactic shock, maintenance of vascular tone through S1PR2 was both more important for survival and more sensitive to fluctuations in circulating S1P levels than maintenance of endothelial barrier function through endothelial S1PR1 (Gazit et al . ). Whether or not S1P also helps maintain vascular tone and blood pressure in septic shock remains to be addressed.…”

“…; Gazit et al . ). Moreover, while circulating S1P is critical for S1PR1 activation on lung endothelium both under homeostasis and during endotoxemia (Camerer et al .…”

“…; Gazit et al . ), the extent to which S1PR1 on brain endothelium encounters circulating S1P before and after BBB disruption is not known. If S1P signaling at the BBB is controlled by local rather than circulating sources, the observed perturbations in the balance of Sphk expression and the up‐regulation of S1P degrading enzymes in the cerebral microvasculature may well impact local signaling.…”