Integrated Stress Response Mediates Early Endothelial Adaptation to Serum Deprivation

Endothelial cells are continuously exposed to fluctuations in circulating blood composi-tion and must rapidly adapt to changes in nutrient and growth factor availability. Here, we investigated how serum deprivation—a model of trophic stress—affects stress adapta-tion pathways in human umbilical vein endothelial cells (HUVECSs), focusing on the in-tegrated stress response (ISR), a key mechanism in cellular adaptation. After 24 hours of serum deprivation, HUVECSs exhibited increased cell death, adoption of an elongated stress-associated morphology, and upregulation of pro-inflammatory genes (ICAM1, PLAU, CCL2). Western blot analysis revealed marked phosphorylation of eIF2α, and quantitative PCR confirmed the induction of ATF4 target genes involved in stress adapta-tion and epigenetic regulation (HDAC1, HDAC8), indicating robust ISR activation. In Matrigel angiogenesis assays, serum-deprived cells showed enhanced angiogenic branching, suggesting a compensatory response. Together, these findings identify growth factor deprivation as a potent trigger of the ISR in endothelial cells and suggest that ISR activation may represent an important component of endothelial adaptation to systemic metabolic challenges.