Endothelial S1P ₁ Signaling Counteracts Infarct Expansion in Ischemic Stroke

Abstract

Rationale: Cerebrovascular function is critical for brain health, and endogenous vascular-protective pathways may provide therapeutic targets for neurological disorders. Sphingosine 1-phosphate (S1P) signaling coordinates vascular functions in other organs, and S1P receptor-1 (S1P 1 ) modulators including fingolimod show promise for the treatment of ischemic and hemorrhagic stroke. However, S1P 1 also coordinates lymphocyte trafficking, and lymphocytes are currently viewed as the principal therapeutic target for S1P 1 modulation in stroke. Objective: To address roles and mechanisms of engagement of endothelial cell (EC) S1P 1 in the naïve and ischemic brain and its potential as a target for cerebrovascular therapy. Methods and Results: Using spatial modulation of S1P provision and signaling, we demonstrate a critical vascular protective role for endothelial S1P 1 in the mouse brain. With an S1P 1 signaling reporter, we reveal that abluminal polarization shields S1P 1 from circulating endogenous and synthetic ligands after maturation of the blood-neural barrier, restricting homeostatic signaling to a subset of arteriolar ECs. S1P 1 signaling sustains hallmark endothelial functions in the naïve brain, and expands during ischemia by engagement of cell-autonomous S1P provision. Disrupting this pathway by EC-selective deficiency in S1P production, export, or the S1P 1 receptor substantially exacerbates brain injury in permanent and transient models of ischemic stroke. By contrast, profound lymphopenia induced by loss of lymphocyte S1P 1 provides modest protection only in the context of reperfusion. In the ischemic brain, EC S1P 1 supports blood-brain barrier (BBB) function, microvascular patency, and the rerouting of blood to hypo-perfused brain tissue through collateral anastomoses. Selective S1P 1 agonism counteracts cortical infarct expansion after middle cerebral artery occlusion by engaging the endothelial receptor pool after BBB penetration. Conclusions: This study provides genetic evidence to support a pivotal role for the endothelium in maintaining perfusion and microvascular patency in the ischemic penumbra that is coordinated by S1P signaling and can be harnessed for neuroprotection with BBB-penetrating S1P 1 agonists.

Glomerular Endothelial Cells Are the Coordinator in the Development of Diabetic Nephropathy

“…S1PR1 is mainly expressed in microvascular endothelial cells and plays a critical role in promoting barrier integrity (64,65), sproutings (62), angiogenesis maturation (66)(67)(68), and nitric oxide generation (69). Endothelium-specific S1PR1knockout mice exhibit impaired blood-brain-barrier integrity and increased adhesion molecule expressions in a middle cerebral artery occlusion-induced stroke model (70)(71)(72). Cardiomyocyte-restricted deletion of S1PR1 shows progressive cardiomyopathy and premature death due to impaired activity of sarcolemmal Na + /H + exchange and increased Ca 2+ sensitivity (73).…”

Sphingosine‐1‐Phosphate, Motor Severity, and Progression in Parkinson's Disease (MARK‐PD)

“…In the central nervous system, S1P receptor agonists improve neurovascular microcirculation, strengthen brain endothelial barrier function thereby limiting plasma and leukocyte extravasation, and support cell survival. 15,16 More specifically, activation of S1PR1 reduces plaque density and amyloid levels in models of Alzheimer's disease and slows down disease progression in mouse models of Huntington's disease. 8,9 From a translational perspective, it is worth mentioning that a clinical pilot trial using fingolimod revealed some beneficial effects of the drug in patients with acute ischemic stroke.…”

Neuroprotective Effects of Danshen Chuanxiongqin Injection Against Ischemic Stroke: Metabolomic Insights by UHPLC-Q-Orbitrap HRMS Analysis

“…Platelets store large amounts of S1P that is only released upon activation (Nitzsche et al, 2021). CD62P, also known as P-selectin, can directly reflect the activation of platelets in vivo and interact with leukocytes to potentiate vascular injury.…”

“…A large number of documents show that Sph kinase (SphK), which phosphorylates Sph to form S1P, is a key regulator of the sphingolipid rheostat (Spiegel and Milstien, 2003), and SphK1 has been proved as the dominant kinase for S1P production in the brain and exert a critical role in "sphingolipid rheostat" (Maceyka et al, 2002;Blondeau et al, 2007). S1P receptors, S1PR1 is amongst the most abundant subtype of S1P receptors in the brain, which plays a crucial role in sustaining hallmark endothelial functions and could be as a regulator for microglial activation following cerebral ischemia (Moon et al, 2015;Nitzsche et al, 2021). S1P can activate platelets, which in turn stimulates the release of S1P into the bloodstream, S1P bind to receptors on the platelet surface, altering cell membrane glycoproteins, exposing fibrinogen receptors, increasing CD62P expression and activation rates and elevating platelet reactivity (Huang et al, 2006).…”