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Mapping S1PR1 Engagement and Ligand Dependence in the Vascular Network
Ilaria Del Gaudio1, Anja Nitzsche1, Kevin Boye1, Khaoula Ben Alaya1, Long Nguyen2, Eric Camerer11 Université Paris Cité, Inserm, PARCC, F-75015 Paris, France
2 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
Background and Aims: Sphingosine 1-phosphate (S1P) maintains vascular homeostasis via S1P receptor-1 (S1PR1). In mice, endothelial selective S1PR1 deficiency is associated with vascular leak, reduced vascular reactivity, hypertension and cognitive impairment. Recent clinical studies have demonstrated significant changes in plasma S1P levels in cardiovascular disease conditions affecting heart, brain, lung and other organs, potentially implicating S1PR1 activation status in disease etiology. However, as S1PR1 has a low nanomolar affinity for S1P and can be engaged not only by circulating ligand but also by endothelial cell-autonomous S1P supply and ligand-independent mechanisms, it is unclear to what extent relative changes in plasma S1P would impact S1PR1 signaling. The degree and vascular zonation of S1PR1 engagement under homeostasis and in the context of cardiovascular risk factors is also incompletely defined.Methods and Results: To address the zonation and ligand dependence of S1PR1 engagement in the vascular endothelium we took advantage of the S1PR1 GS reporter mice to map β-arrestin recruitment to S1PR1 under homeostasis and after exposure to cardiovascular risk factors. S1PR1 signaling in the blood endothelium was observed in capillaries in the lung but restricted to resistance-size arteries in other organs. Accordingly, arterial endothelia cell (EC)-selective S1PR1 deficiency was associated with albumin extravasation comparable to pan-EC S1PR1 deficiency in the brain but not the lung. Receptor engagement did not depend on sex or age but was modestly increased within arteries of mice with hypertension and type 1 diabetes. Consistent with the widespread expression of S1PR1, signaling nevertheless expanded to capillary and venous endothelial cells in response to synthetic agonist infusion, although not to all S1PR1 expressing cells. S1PR1 signaling was reduced and vascular leak increased in the absence of hematopoietic but not vessel wall S1P production, and both were sensitive to graded reductions in plasma S1P levels with an apparent saturation threshold around 50% of normal plasma levels. Accordingly, ECs contributed little or no S1P to plasma in naïve mice, and plasma S1P deficiency was associated blood-brain barrier dysfunction and impaired hypercapnia-induced vasodilation. Conclusions: Our results illustrate that S1PR1 is activated primarily by plasma S1P to regulate vascular tone and integrity under homeostasis and that such activation is highly restricted in the blood endothelium. S1PR1 engagement is surprisingly sensitive to relative reductions in plasma S1P. These observations highlight the relevance of plasma S1P as a biomarker for endothelial function in both lung and brain.Speakers
Ilaria Del Gaudio