Modern western dietary habits and low physical activity cause metabolic abnormalities and abnormally elevated levels of metabolites such as low-density lipoprotein, which can lead to immune cell activation, and inflammatory reactions, and atherosclerosis. Appropriate stimulation of vascular endothelial cells can confer protective responses against inflammatory reactions and atherosclerotic conditions. This study aims to determine whether a designed optogenetic approach is capable of affecting functional changes in vascular endothelial cells and to evaluate its potential for therapeutic regulation of vascular inflammatory responses . We employed a genetically engineered, blue light-activated Ca channel switch molecule that utilizes an endogenous store-operated calcium entry system and induces intracellular Ca influx through blue light irradiation and observed an increase in intracellular Ca in vascular endothelial cells. Ca-dependent activation of the nuclear factor of activated T cells and nitric oxide production were also detected. Microarray analysis of Ca-induced changes in vascular endothelial cells explored several genes involved in cellular contractility and inflammatory responses. Indeed, there was an increase in the gene expression of molecules related to anti-inflammatory and vasorelaxant effects. Thus, a combination of human blue light-activated Ca channel switch 2 (hBACCS2) and blue light possibly attenuates TNFα-induced inflammatory NF-κB activity. We propose that extrinsic cellular Ca regulation could be a novel approach against vascular inflammation.