Abstract
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 G1 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.