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Platelet-derived growth factor receptor-β (PDGFR-β) has been reported to promote phenotypic transformation of vascular smooth muscle cells (VSMCs). The purpose of this study was to investigate the role of the PDGFR-β/IRF9/SIRT-1/NF-κB pathway in VSMC phenotypic transformation after subarachnoid hemorrhage (SAH). SAH was induced using the endovascular perforation model in Sprague-Dawley rats. PDGFR-β small interfering RNA (siRNA) and IRF9 siRNA were injected intracerebroventricularly 48 h before SAH. SIRT1 activator (resveratrol) and inhibitor (EX527) were administered intraperitoneally 1 h after SAH induction. Twenty-four hours after SAH, the VSMC contractile phenotype marker α-smooth muscle actin (α-SMA) decreased, whereas the VSMC synthetic phenotype marker embryonic smooth muscle myosin heavy chain (Smemb) increased. Both PDGFR-β siRNA and IRF9 siRNA attenuated the induction of nuclear factor-κB (NF-κB) and enhanced the expression of α-SMA. The SIRT1 activator (resveratrol) preserved VSMC contractile phenotype, significantly alleviated neurological dysfunction, and reduced brain edema. However, these beneficial effects of PDGFR-β siRNA, IRF9 siRNA and resveratrol were abolished by the SIRT1 inhibitor (EX527). This study shows that PDGFR-β/IRF9/SIRT-1/NF-κB signaling played a role in the VSMC phenotypic transformation after SAH. Inhibition of this signaling cascade preserved the contractile phenotype of VSMCs, thereby improving neurological outcomes following SAH.

Glioblastoma angiogenesis is critical for tumor growth, making it an appealing target for treatment development. BAY1143269 is a novel inhibitor of mitogen‐activated protein kinase interacting serine/threonine‐protein kinase 1 (MKN1) and has potent anti‐cancer activity. We identified BAY1143269 as an angiogenesis inhibitor, by in vitro and in vivo glioblastoma angiogenesis models. BAY1143269 inhibited the capillary network formation of glioblastoma microvascular endothelial cells (GMECs), particularly the early stage of tubular structure formation. It also inhibited migration and proliferation, and induced apoptosis of GMECs isolated from glioblastoma patients. We found that BAY1143269 acted on GMECs by suppressing the eukaryotic translation initiation factor 4E (eIF4E) and eIF4E‐mediated expression of oncogenic proteins, including those involved in cell cycle, epithelial‐mesenchymal transition (EMT), and pro‐survival. In addition, BAY1143269 suppressed eIF4E phosphorylation, inhibited proliferation, and induced apoptosis of glioblastoma cells. Interestingly, it reduced vascular endothelial growth factor (VEGF) level in tumor cells and culturing medium, demonstrating the inhibitory effect of BAY1143269 on tumor proangiogenic microenvironment. We finally challenged BAY1143269 on the glioblastoma xenograft mice model and observed a significant tumor growth reduction without toxicity in mice receiving oral BAY1143269. Immunoblotting analysis demonstrated significantly less phosphorylated‐eIF4E (p‐eIF4E), cluster of differentiation 31 (CD31) (microvascular endothelial cell marker), and VEGF in tumors from drug‐treated mice. In summary, the inhibition of glioblastoma angiogenesis with BAY1143269 may provide an alternative approach for anti‐glioblastoma therapy. [ABSTRACT FROM AUTHOR]

Background: The treatment of posterior inferior cerebellar artery aneurysms is controversial. Recently, flow diverters have emerged as an attractive treatment option. Here, we performed a systematic review and meta-analysis of the angiographic and clinical outcomes of flow diverter-treated posterior inferior cerebellar artery aneurysms. Methods: We searched the PubMed, EMBASE and Web of Science databases for studies published from inception to January 2021. We included studies that described flow diverters procedures for posterior inferior cerebellar artery aneurysms with ≥2 patients. The outcomes were the complete occlusion rate and flow diverter-related complication rate. Meta-analysis was performed using a random or fixed effects model based on heterogeneity. Results: We included six studies involving 46 posterior inferior cerebellar artery aneurysms. There were 14 ruptured aneurysms. All flow diverters were successfully released and the technical success rate was 100%. The complete occlusion rate was 81% (95% confidence interval = 65–93%; I 2 = 0.00%; P < 0.01). The flow diverter-related complication rate was 18% (95% confidence interval = 5–36%; I 2 = 0.00%; P < 0.01). One patient died of rebleeding. The mortality rate was <1% (95% confidence interval = -1–1%; I 2 = 0.00%; P = 0.951). Conclusions: Treatment of posterior inferior cerebellar artery aneurysms with flow diverters is feasible and carries a high degree of technical success. However, this treatment is underutilized in patients with posterior inferior cerebellar artery aneurysms due to a higher complication rate and lower occlusion rate compared with clipping and traditional endovascular treatment. Further well-designed prospective and randomized studies are required to fully understand the effects of flow diverters especially in posterior inferior cerebellar artery aneurysms patients requiring endovascular treatment. [ABSTRACT FROM AUTHOR]