Sphingosine-1-phosphate Signaling in the Peripheral Vasculature. – SphiPerVasc

1) Generation and validation of transgenic mice with tissue specific deficiencies in S1P production or signaling.
2) Ex vivo assessment of resistance artery function and whole organ resistance using pressure myography, wire myography and the flow/pressure relationship in isolated perfused kidneys.
3) Assessment of cardiac function and organ vascular resistance by ultrasonography.
4) Measurements of blood pressure by the tail cuff method and by telemetry based recordings of aortic blood pressure.

We have demonstrated an important role for S1P signaling through S1PR1 in supporting flow-mediated dilation in isolated mesenteric and cerebral arteries and in promoting tissue perfusion in the ischemic penumbra after ischemic stroke. In the context of cerebral ischemia, we have shown that endothelial S1PR1 activation depends on cell-autonomous S1P production and export.

We are currently exploring mechanisms of S1PR1 activation in other organs and the importance of circulating vs. vessel wall sources of S1P production for blood pressure homeostasis.

Original article:

Endothelial S1P1 Signaling Counteracts Infarct Expansion in Ischemic Stroke. Nitzsche A, Poittevin M, Benarab A, Bonnin P, Faraco G, Uchida H, Favre J, Garcia-Bonilla L, Garcia MCL, Léger PL, Thérond P, Mathivet T, Autret G, Baudrie V, Couty L, Kono M, Chevallier A, Niazi H, Tharaux PL, Chun J, Schwab SR, Eichmann A, Tavitian B, Proia RL, Charriaut-Marlangue C, Sanchez T, Kubis N, Henrion D, Iadecola C, Hla T, Camerer E. Circ Res. 2021 Feb 5;128(3):363-382. doi: 10.1161/CIRCRESAHA.120.316711.

Invited review:

La signalisation endothéliale par la sphingosine 1-phosphate maintient la perfusion corticale au cours de la phase aiguë de l’accident vasculaire cerebral ischémique. Nitzsche A, Poittevin M, Benarab A, Bonnin P, Camerer E. medicine/sciences n° 8-9, vol. 37, août-septembre 2021

Patent filed: Methods for stimulation cerebrovascular function/EP20305046.3.

Mammals are endowed with a high-pressure cardiovascular system that maintains perfusion of tissues at considerable distance from the heart and constantly fine-tunes inter- and intra-regional blood supply according to metabolic needs. To prevent microvascular damage, the system requires the pressure in conduit arteries to be efficiently dampened before blood reaches capillary beds. This is achieved by the high muscular tone of so-called resistance arteries, which also provides the vasodilatory potential needed for dynamic local and systemic redistribution of cardiac output. Resistance artery diameter is modulated through sympathetic innervation, hormones, shear stress, and mechanical pressure, and is controlled locally by the release of endothelial mediators that regulate the contractile state of vascular smooth muscle cells. The sophistication of the high-pressure system with its multitude of regulatory mechanisms also renders it sensitive to environmental perturbations. Vascular reactivity, which requires both vascular tone and endothelial function, is reduced with age and compromised by cardiovascular risk factors; its deterioration is both an early indicator of cardiovascular disease and a contributor to disease escalation, organ damage, and morbidity. Mechanisms that regulate vascular reactivity may thus provide novel drug targets for cardiovascular disease.

Sphingosine-1-phosphate (S1P) is an abundant plasma lipid that is carried on high-density lipoproteins (HDL) and that mediates many of their vascular protective functions through activation of G protein-coupled receptor signaling. S1P signaling is essential for the development and the sustained integrity of the cardiovascular system, as well as for the trafficking of lymphocytes and thus for adaptive immunity. While not classically considered amongst factors that regulate microvascular function, a growing body of evidence suggests that S1P may sustain pressure-induced (myogenic) tone and mediate endothelial shear stress sensing and dilatation in resistance arteries. Remarkably, modulation of the S1P pathway was also recently shown to either fully reverse or fully prevent the development of hypertension in mouse models, although it is unclear whether this was by targeting actions on resistance arteries, the immune system, or other organs. It is also unclear how an omnipresent plasma lipid would drive such a dynamic process. Thus, while emerging evidence argues that S1P may be a key mediator of microvascular function, its roles and mechanisms of action remain to be fully understood and widely appreciated. In this project, two French research laboratories and one clinical practitioner with complementary tools and expertise in mouse genetics, signaling, and analysis of vascular anatomy and function, will join forces to explore how S1P signaling is elicited in the peripheral vasculature. Using series of novel mouse lines engineered for temporal and spatial deficiency in S1P production and S1P receptors, we will address the potential of blood- and vessel wall-derived S1P to modulate vascular function in isolated vessels and organs and in the intact organism. We will further address whether if vascular functions of S1P account for its impact on the development of hypertension.

Preliminary results generated by the consortium support the premise that S1P signaling plays important roles in the regulation of vascular reactivity and development of hypertension. We expect that the studies outlined in this proposal will inform on how S1P signaling is engaged to regulate resistance artery function and blood pressure, and thus on the potential diagnostic value of blood S1P for microvascular health and the development of hypertension. The insight gained should also inform on the potential of selectively targeting components of the S1P pathway for the maintenance of microvascular homeostasis.