STTT major progress!

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iNature revascularization and angiogenesis, as substrates of persistent collateral circulation, play a critical role in determining the severity and clinical outcome of acute ischemic stroke (AIS) caused by large vessel occlusion (LVO)
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The development of auxiliary biomarkers to help identify and monitor collateral status will aid in stroke diagnosis and prognosis
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On January 7, 2022, Wang Wei's team from Huazhong University of Science and Technology published a research paper titled "FSAP aggravated endothelial dysfunction and neurological deficits in acute ischemic stroke due to large vessel occlusion" online at Signal Transduction and Targeted Therapy (IF=18).
To screen for potential biomarkers, proteomic analysis was performed to identify those distinct plasma protein profiles in AIS due to LVO with different collateral states
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Interestingly, this study found that plasma factor VII-activating protease (FSAP) levels were significantly increased in those AIS patients with poor collateral circulation and were associated with worse neurological outcomes
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In addition, both in vitro and in vivo models of ischemic stroke were used to explore the pathological mechanism of FSAP in endothelial dysfunction
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This study demonstrates that the FSAP inhibitor high molecular weight hyaluronic acid (HMW-HA) enhances pro-angiogenic angiogenic factors, improves the integrity of the cerebral blood barrier, and promotes newly formed cerebral microvessels in ischemia, thereby improving neurological function
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To elucidate pathways that may contribute to revascularization during LVO, this study applied transcriptomic analysis by unbiased RNA sequencing and showed that Wnt signaling is highly involved in FSAP-mediated endothelial dysfunction
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Notably, inhibition of Wnt5a largely reversed the protective effect of HMW-HA treatment, implying that FSAP may exacerbate endothelial dysfunction and neurological deficits by modulating Wnt5a signaling
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Therefore, FSAP may represent a potential biomarker of collateral status after LVO and a promising therapeutic target to explore in stroke treatment
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Approximately 40% of acute ischemic strokes are caused by proximal intracranial large vessel occlusion (LVO), which is also associated with poor clinical outcomes
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Current management strategies for patients with LVO-induced ischemic stroke include early reperfusion with intravenous tissue plasminogen activator (tPA) and/or intra-arterial thrombectomy
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However, most LVO stroke patients remain untreated because their diagnosis is outside the optimal time window for acute reperfusion therapy or because they cannot reach major stroke centers where thrombectomy can be performed
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After an artery is occluded, alternative blood flow pathways called collaterals can maintain activity in areas of the brain for a period of time
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Infarct growth varies from person to person and is regulated by collateral blood flow and inflammation secondary to ischemia
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There is increasing clinical evidence that collateral circulation status is an independent predictor of outcome and response to recanalization in patients with ischemic stroke
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Furthermore, well-maintained collateral circulation can limit infarct growth over time in persistent LVO
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Angiogenic endothelial cells and the formation of new blood vessels, involved in vascular proliferation, also affect ongoing collateral circulation and play a crucial role in determining the outcome and severity of ischemic injury
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Advanced neuroimaging modalities that provide angiographic and perfusion information may help identify collateral status and guide therapeutic intervention
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Digital subtraction angiography (DSA) is considered the gold standard for imaging collateral states
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However, its invasiveness limits its application
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Conversely, the noninvasive nature of CT angiography makes it a good option for assessing collateral status in acute stroke patients
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However, methods for assessing collateral status based on non-contrast CT or magnetic resonance imaging (MRI) are lacking and require direct comparison with DSA
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Therefore, a simple, fast, and sensitive technique for collateral monitoring, such as blood testing, is critical
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Article pattern diagram (image from Signal Transduction and Targeted Therapy) As mentioned previously, identification and monitoring of molecular biomarkers in AIS will aid in stroke diagnosis, prognosis, and treatment strategies
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Several biomarkers were found to be associated with collateral status, however, the incidence and underlying pathophysiology of these biomarkers remain unclear in the general population
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In the present study, proteomic and ELISA analyses were used to screen for differentially expressed proteins between patients with LVO-induced AIS but different collateral status
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This study demonstrates that plasma FSAP levels are indicative of collateral status and have potential prognostic value for neurological function at 3 months
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This study further shows that FSAP can reduce collateral blood flow in the acute phase and inhibit collateral formation in experimental ischemic stroke
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Since high levels of FSAP may lead to disturbances in collagen production and endothelial function, the signaling pathways involved were explored
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These findings are not only fundamentally important for understanding collateral formation, but also provide the information needed to develop persistent collateral therapy for patients with persistent LVO
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