Abstract
Revascularization and angiogenesis, as substrates of sustained collateral circulation, play a crucial role in determining the severity and clinical outcome of acute ischemic stroke (AIS) due to large vessel occlusion (LVO). Developing an adjunct biomarker to help identify and monitor collateral status would aid stroke diagnosis and prognosis. To screen the potential biomarkers, proteomic analysis was performed in this study to identify those distinct plasma protein profiles in AIS due to LVO with different collateral status. Interestingly, we found that levels of Plasma Factor VII Activating Protease (FSAP) significantly increased in those AIS patients with poor collaterals, and were correlated with worse neurological outcome. Furtherly, both in vitro and in vivo models of ischemic stroke were used to explore pathological mechanisms of FSAP in endothelial dysfunction. We demonstrated that the FSAP inhibitor, high-molecular-weight hyaluronan (HMW-HA), enhanced the pro-angiogenic vascular factors, improved the integrity of brain blood barrier, and promoted newly formed cerebral microvessels in the ischemic penumbra, consequently improving neurological function. To elucidate the pathways that might contribute to revascularization during LVO, we applied transcriptomic analysis via unbiased RNA sequencing and showed that Wnt signaling was highly involved in FSAP mediated endothelial dysfunction. Notably, inhibition of Wnt5a largely reversed the protective effects from HMW-HA treatment, implying that FSAP might aggravate endothelial dysfunction and neurological deficits by regulating Wnt5a signaling. Therefore, FSAP may represent a potential biomarker for collateral status after LVO and a promising therapeutic target to be explored in the treatment of stroke.
Highlights
40% of acute ischemic strokes are caused by proximal intracranial large vessel occlusions (LVO) that are associated with poor clinical outcomes.[1,2]
Plasma FSAP levels increased in patients with ischemic stroke and were correlated with 3-month outcome Baseline characteristic details of the patient and control participants in the study are summarized in Supplementary Tables 1–2
Data is expressed as mean ± SD; n = 5–7 for each group; n.s. not significant, **p < 0.01, ***p < 0.001 versus Control group, n.s. not significant, #p < 0.05, ##p < 0.01, ###p < 0.001 versus vehicle group by one-way analysis of variance (ANOVA) followed by Tukey’s multiple comparison tests. d, e Proangiogenic factors expression was detected by Western blot. d Representative Western blot images and e quantitative analysis
Summary
40% of acute ischemic strokes are caused by proximal intracranial large vessel occlusions (LVO) that are associated with poor clinical outcomes.[1,2] Current management strategies for patients with ischemic stroke due to LVO include early reperfusion with intravenous tissue-type plasminogen activator (tPA) and/or intra-arterial thrombectomy.[3]. Angiogenesis involving proliferation of endothelial cells and formation of new vessels, affects sustained collateral circulation and plays a crucial role in determining the outcome and severity of ischemic injury.[7]
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