Systems Biology Analysis of Temporal Dynamics That Govern Endothelial Response to Cyclic Stretch

This study mapped how equibiaxial cyclic stretch magnitude drives a shift between atheroprotective and atheroprone endothelial phenotypes using a systems-biology framework. Primary HUVECs were subjected to physiological (10% change in radius,Δr) versus pathological (20%Δr) equibiaxial cyclic stretch for 24 h, followed by transcriptome profiling (RNA-seq) and pathway/network analyses. Pathological stretch induced four dominant response programs: (1) cell-cycle regulation (E2F-associated targets and proliferative signaling), (2) inflammatory/interferon-associated signaling (including STAT1/HIF1A/CCL2-linked networks), (3) fatty-acid metabolism remodeling consistent with an atheroprone metabolic state, and (4) mTOR signaling modulation governed by an identified regulatory transcription-factor network (JUN,MYC,ATF2,TERF1,CREB1,CEBPG,NR3C1,JUNB). Functional validation included qPCR for key regulators (E2F1,JUNB,ATF2,STAT1), cytoskeletal/junctional remodeling (actin stress fibers and VE-cadherin redistribution), and live-cell stiffness mapping by AFM showing dose-dependent softening with stretch that was reversed by rapamycin, implicating mTOR in stretch-dependent mechanical phenotype control. Comparative reanalysis with published shear-stress datasets suggested 10% stretch clusters with pulsatile shear (atheroprotective) and 20% stretch with oscillatory shear (atheroprone), supporting shared regulatory logic across hemodynamic stimuli.