Tissue Specificity: SOCE: Implications for Ca²⁺ Handling in Endothelial Cells

Abstract

Many cellular functions of the vascular endothelium are regulated by fine-tuned global and local, microdomain-confined changes of cytosolic free Ca²⁺ ([Ca²⁺]_i). Vasoactive agonist-induced stimulation of vascular endothelial cells (VECs) typically induces Ca²⁺ release through IP₃ receptor Ca²⁺ release channels embedded in the membrane of the endoplasmic reticulum (ER) Ca²⁺ store, followed by Ca²⁺ entry from the extracellular space elicited by Ca²⁺ store depletion and referred to as capacitative or store-operated Ca²⁺ entry (SOCE). In vascular endothelial cells, SOCE is graded with the degree of store depletion and controlled locally in the subcellular microdomain where depletion occurs. SOCE provides distinct Ca²⁺ signals that selectively control specific endothelial functions: in calf pulmonary artery endothelial cells, the SOCE Ca²⁺ signal drives nitric oxide (an endothelium-derived relaxing factor of the vascular smooth muscle) production and controls activation and nuclear translocation of the transcription factor NFAT. Both cellular events are not affected by Ca²⁺ signals of comparable magnitude arising directly from Ca²⁺ release from intracellular stores, clearly indicating that SOCE regulates specific Ca²⁺-dependent cellular tasks by a unique and exclusive mechanism. This review discusses the mechanisms of intracellular Ca²⁺ regulation in vascular endothelial cells and the role of store-operated Ca²⁺ entry for endothelium-dependent smooth muscle relaxation and nitric oxide signaling, endothelial oxidative stress response, and excitation-transcription coupling in the vascular endothelium.