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Flow induced-endothelial phenotypic transition contributes to Intracranial Aneurysm

ABSTRACT: Rupture of intracranial aneurysms (IAs) represents a life-threatening cerebrovascular event associated with high morbidity and mortality. Elucidating the pathological mechanisms driving IA initiation and progression is critical for developing an effective therapeutic strategy. Endothelial cell (EC) dysfunction is known to contribute to IA pathogenesis. Hemodynamic force— particularly fluid shear stress (FSS) are well-established mediators of IA pathogenesis, yet the mechanisms by which FSS triggers endothelial injury remain incompletely understood. In this study, single-cell sequencing of human revealed that endothelial-to-mesenchymal transition (EndMT) as a hallmark feature of early-stage IA formation, whereas EndMT was markedly attenuated in ruptured aneurysms. Using a mouse IA model and an in vitro parallel-plate flow chamber system, we demonstrated that exposure to high laminar FSS (HSS) promotes EndMT in endothelial cells, concomitant with actin cytoskeletal reorganization and nuclear translocation of Yes-associated protein (YAP). In contrast, under low or vortex flow (VSS) conditions characteristic of advanced IA stages, endothelial cells undergo phenotypic reversion—evidenced by reduced expression of cytoskeletal proteins and cytoplasmic sequestration of YAP. Notably, endothelial inflammation escalates progressively throughout IA development and contributes directly to sustained endothelial dysfunction. Pharmacological inhibition of actin polymerization effectively suppressed EndMT in the early stage but failed to restore endothelial integrity during the late stage. Collectively, these findings identify FSS–cytoskeleton–YAP–EndMT axis as a stage-specific, druggable pathway with translational potential for early intervention in intracranial aneurysm disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE329653 | GEO | 2026/05/05

REPOSITORIES: GEO

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Project description:<p>Intracranial aneurysms (IAs) are benign cerebrovascular maladies characterized by pathological dilatation in the walls of intracranial arteries. However, spontaneous subarachnoid hemorrhage (SAH) resulting from aneurysm rupture poses a grave threat to the patient's life. Accumulating evidence implicates gut ecological dysregulation in the pathogenesis of IAs. Nevertheless, the relevance of gut dysbiosis to the rupture of IAs remains unknown. In this study, altogether 124 fecal samples were employed for microbiome sequencing by third-generation 16s rRNA sequencing, while 160 fecal samples were sequenced for metabolomics sequencing by liquid chromatography-mass spectroscopy techniques. Furthermore, the stool samples from IAs and healthy family controls were partitioned into two cohorts: the discovery set and the validation set for mutual cross-validation. Differential gut microbiota and metabolites associated with ruptured intracranial aneurysms (RIAs) were identified. Additionally, a superior risk assessment model for RIAs was constructed utilizing these differential species and metabolites. Subsequent integrated metabolomics and microbiomics analyses have uncovered a profound link between the dysregulation of unsaturated fatty acid and essential amino acid metabolic pathways and the rupture of IAs. This metabolic imbalance is attributed to alternations in the gut microbiota composition. Furthermore, we further revealed alterations in the gut flora of patients with IAs at high-risk rupture locations, incorporating the clinical characteristics. Finally, 30 peripheral blood and paired cerebrospinal fluid samples were tested to confirm variations in α-linolenic acid, linoleic acid and butyric acid concentrations among IA patients. This study underscores the crucial role of gut microbiota and metabolisms dysbiosis in IAs formation, while also highlighting a novel risk factor for aneurysm rupture. The identification and validation of differential species and metabolites provide new assessment biomarkers against IAs rupture.</p>

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Flow induced-endothelial phenotypic transition contributes to Intracranial Aneurysm

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