A mechanistic systems biology model of brain microvascular endothelial cell signaling reveals dynamic pathway-based therapeutic targets for brain ischemia

• DOI: 10.1016/j.redox.2024.103415
• Publication Date: 2024-11-05T02:13:24Z
• Authors: Geli Li; Yuchen Ma; Sujie Zhang; Wen Lin; Xinyi Yao; Yating Zhou; Yanyong Zhao; Qi Rao; Yuchen Qu; Yuan Gao; Lianmin Chen; Yu Zhang; Feng Han; Meiling Sun; Chen Zhao
• Keywords: Brain ischemia

Ischemic stroke is a significant threat to human health. Currently, there lack of effective treatments for stroke, and progress in new neuron-centered drug target development relatively slow. On the other hand, studies have demonstrated that brain microvascular endothelial cells (BMECs) are crucial components neurovascular unit play pivotal roles ischemic progression. To better understand complex multifaceted BMECs regulation pathophysiology facilitate BMEC-based discovery, we utilized transcriptomics-informed systems biology modeling approach constructed mechanism-based computational multipathway model systematically investigate BMEC function its modulatory potential. Extensive multilevel data regarding pathway signal transduction biomarker expression under various pathophysiological conditions were used quantitative calibration validation, generated dynamic phenotype maps response stroke-related stimuli identify potential determinants fate stress conditions. Through high-throughput sensitivity analyses virtual perturbations model-based single cells, our predicted targeting succinate could effectively reverse detrimental cell oxygen glucose deprivation/reoxygenation, condition mimics pathogenesis, experimentally validated utility this terms regulating inflammatory factor production, free radical generation tight junction protection vitro vivo. Our work first complementarily couples transcriptomic analysis with mechanistic systems-level study endothelium-based therapeutic targets stroke.