Dataset Information

Endothelial S1P₁ 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. S1P (Sphingosine 1-phosphate) signaling coordinates vascular functions in other organs, and S1P₁ (S1P receptor-1) modulators including fingolimod show promise for the treatment of ischemic and hemorrhagic stroke. However, S1P₁ also coordinates lymphocyte trafficking, and lymphocytes are currently viewed as the principal therapeutic target for S1P₁ modulation in stroke.

Objective

To address roles and mechanisms of engagement of endothelial cell S1P₁ in the naive 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 S1P₁ in the mouse brain. With an S1P₁ signaling reporter, we reveal that abluminal polarization shields S1P₁ from circulating endogenous and synthetic ligands after maturation of the blood-neural barrier, restricting homeostatic signaling to a subset of arteriolar endothelial cells. S1P₁ signaling sustains hallmark endothelial functions in the naive brain and expands during ischemia by engagement of cell-autonomous S1P provision. Disrupting this pathway by endothelial cell-selective deficiency in S1P production, export, or the S1P₁ receptor substantially exacerbates brain injury in permanent and transient models of ischemic stroke. By contrast, profound lymphopenia induced by loss of lymphocyte S1P₁ provides modest protection only in the context of reperfusion. In the ischemic brain, endothelial cell S1P₁ supports blood-brain barrier function, microvascular patency, and the rerouting of blood to hypoperfused brain tissue through collateral anastomoses. Boosting these functions by supplemental pharmacological engagement of the endothelial receptor pool with a blood-brain barrier penetrating S1P₁-selective agonist can further reduce cortical infarct expansion in a therapeutically relevant time frame and independent of reperfusion.

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 blood-brain barrier-penetrating S1P₁ agonists.

SUBMITTER: Nitzsche A

PROVIDER: S-EPMC7874503 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:In stroke care, the extent of irreversible brain injury, termed infarct core, plays a key role in determining eligibility for acute treatments, such as intravenous thrombolysis and endovascular reperfusion therapies. Many of the pivotal randomized clinical trials testing those therapies used MRI Diffusion-Weighted Imaging (DWI) or CT Perfusion (CTP) to define infarct core. Unfortunately, these modalities are not available 24/7 outside of large stroke centers. As such, there is a need for accurate infarct core determination using faster and more widely available imaging modalities including Non-Contrast CT (NCCT) and CT Angiography (CTA). Prior studies have suggested that CTA provides improved predictions of infarct core relative to NCCT; however, this assertion has never been numerically quantified by automatic medical image computing pipelines using acquisition protocols not confounded by different scanner manufacturers, or other protocol settings such as exposure times, kilovoltage peak, or imprecision due to contrast bolus delays. In addition, single-phase CTA protocols are at present designed to optimize contrast opacification in the arterial phase. This approach works well to maximize the sensitivity to detect vessel occlusions, however, it may not be the ideal timing to enhance the ischemic infarct core signal (ICS). In this work, we propose an image analysis pipeline on CT-based images of 88 acute ischemic stroke (AIS) patients drawn from a single dynamic acquisition protocol acquired at the acute ischemic phase. We use the first scan at the time of the dynamic acquisition as a proxy for NCCT, and the rest of the scans as a proxy for CTA scans, with bolus imaged at different brain enhancement phases. Thus, we use the terms "NCCT" and "CTA" to refer to them. This pipeline enables us to answer the questions "Does the injection of bolus enhance the infarct core signal?" and "What is the ideal bolus timing to enhance the infarct core signal?" without being influenced by aforementioned factors such as scanner model, acquisition settings, contrast bolus delay, and human reader errors. We use reference MRI DWI images acquired after successful recanalization acting as our gold standard for infarct core. The ICS is quantified by calculating the difference in intensity distribution between the infarct core region and its symmetrical healthy counterpart on the contralateral hemisphere of the brain using a metric derived from information theory, the Kullback-Leibler divergence (KL divergence). We compare the ICS provided by NCCT and CTA and retrieve the optimal timing of CTA bolus to maximize the ICS. In our experiments, we numerically confirm that CTAs provide greater ICS compared to NCCT. Then, we find that, on average, the ideal CTA acquisition time to maximize the ICS is not the current target of standard CTA protocols, i.e., during the peak of arterial enhancement, but a few seconds afterward (median of 3 s; 95% CI [1.5, 3.0]). While there are other studies comparing the prediction potential of ischemic infarct core from NCCT and CTA images, to the best of our knowledge, this analysis is the first to perform a quantitative comparison of the ICS among CT based scans, with and without bolus injection, acquired using the same scanning sequence and a precise characterization of the bolus uptake, hence, reducing potential confounding factors.

Dataset Information

Endothelial S1P₁ Signaling Counteracts Infarct Expansion in Ischemic Stroke.

Rationale

Objective

Methods and results

Conclusions

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OmicsDI is part of the ELIXIR infrastructure

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Endothelial S1P1 Signaling Counteracts Infarct Expansion in Ischemic Stroke.

Rationale

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Methods and results

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Endothelial S1P₁ Signaling Counteracts Infarct Expansion in Ischemic Stroke.