Deng Hanqiang, Rukhlenko Oleksii S, Joshi Divyesh, Hu Xiaoyue, Junk Philipp, Tuliakova Anna, Kholodenko Boris N, Schwartz Martin A
Yale Cardiovascular Research Center, Yale School of Medicine, New Haven, CT 06511, USA.
Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06511, USA.
Sci Adv. 2025 Jan 3;11(1):eado9970. doi: 10.1126/sciadv.ado9970.
Fluid shear stress (FSS) from blood flow sensed by vascular endothelial cells (ECs) determines vessel behavior, but regulatory mechanisms are only partially understood. We used cell state transition assessment and regulation (cSTAR), a powerful computational method, to elucidate EC transcriptomic states under low shear stress (LSS), physiological shear stress (PSS), high shear stress (HSS), and oscillatory shear stress (OSS) that induce vessel inward remodeling, stabilization, outward remodeling, or disease susceptibility, respectively. Combined with a publicly available database on EC transcriptomic responses to drug treatments, this approach inferred a regulatory network controlling EC states and made several notable predictions. Particularly, inhibiting cell cycle-dependent kinase (CDK) 2 was predicted to initiate inward remodeling and promote atherogenesis. In vitro, PSS activated CDK2 and induced late G cell cycle arrest. In mice, EC deletion of CDK2 triggered inward artery remodeling, pulmonary and systemic hypertension, and accelerated atherosclerosis. These results validate use of cSTAR and identify key determinants of normal and pathological artery remodeling.
血管内皮细胞（ECs）感知到的血流产生的流体剪切应力（FSS）决定血管行为，但其调控机制仅被部分理解。我们使用细胞状态转变评估与调控（cSTAR）这一强大的计算方法，来阐明在低剪切应力（LSS）、生理剪切应力（PSS）、高剪切应力（HSS）和振荡剪切应力（OSS）下的内皮细胞转录组状态，这些剪切应力分别诱导血管向内重塑、稳定、向外重塑或疾病易感性。结合一个公开的关于内皮细胞对药物治疗转录组反应的数据库，该方法推断出一个控制内皮细胞状态的调控网络，并做出了几个显著的预测。特别地，预测抑制细胞周期依赖性激酶（CDK）2会引发向内重塑并促进动脉粥样硬化的发生。在体外，PSS激活CDK2并诱导晚期G期细胞周期停滞。在小鼠中，内皮细胞中CDK2的缺失引发动脉向内重塑、肺动脉高压和全身高血压，并加速动脉粥样硬化。这些结果验证了cSTAR的用途，并确定了正常和病理性动脉重塑的关键决定因素。
