The sarco/endoplasmic reticulum calcium ATPase (SERCA) is a critical mediator of intracellular calcium homeostasis, actively transporting calcium from the cytosol into the sarco/endoplasmic reticulum in eukaryotic cells. Regulation of SERCA is important for vascular endothelial cell (VEC) homeostasis. These cells have distinct calcium signaling demands, and dysfunctional calcium handling is a feature of vascular pathologies such as stroke and atherosclerosis. SERCA activity in VECs is modulated by endoregulin (ELN), a newly identified SERCA-inhibiting micropeptide. Here, we investigated ELN’s role in endothelial adaptation to hypoxic stress, central to many vascular diseases. Knockdown of ELN in human umbilical venous endothelial cells (HUVECs) impaired barrier integrity, significantly reduced cell migration and impaired angiogenic function under hypoxia. Transcriptomic analysis revealed marked reductions (∼70%) in key endothelial regulators, including VEGF and eNOS, implicating ELN in redox balance and angiogenic signaling. Reactive oxygen species (ROS) were quantified with a ROS indicator, H2DCFD. ROS production was increased by ∼50% after ELN knockdown, implicating oxidative stress as a driver of dysfunction. qPCR analysis showed upregulation of VCAM1, ICAM1, and E-selectin, driving ROS-induced endothelial activation and inflammation, all indicators associated with disease progression. Together, these findings suggest ELN as a key regulator of endothelial homeostasis, highlighting the potential for therapeutic targeting of ELN in vascular diseases, such as stroke, atherosclerosis, and ischemia-reperfusion injury. Strategies aimed at enhancing ELN function or mimicking its activity could improve vascular repair, maintaining barrier integrity and promoting migration under hypoxic stress.
Robia et al. (Sun,) studied this question.