Consistent daylight oscillations and abundant oxygen availability are fundamental to human health. While both are connected from an evolutionary and cellular perspective, only oxygen is an established therapy in cardiovascular medicine. We investigated the intersection between light-(Period 2, PER2) and oxygen-(hypoxia inducible factor, HIF1A) sensing pathways in cellular adaptation to myocardial ischemia. We demonstrate that intense light is cardioprotective via circadian PER2 amplitude enhancement, mimicking hypoxia elicited adenosine-and HIF1A-metabolic adaptation to myocardial ischemia under normoxic conditions. Whole-genome array analysis from uninjured, intense light exposed wildtype or Per2 -/mice and myocardial ischemia in endothelial-specific PER2 deficient mice uncover a critical role for intense light in maintaining endothelial barrier function via light-enhanced HIF1A transcription. A proteomics screen in human endothelia reveals a dominant role for PER2 in metabolic reprogramming to hypoxia via mitochondrial translocation, TCA cycle enzyme activity regulation and HIF1A transcriptional adaption to hypoxia. Translational investigation of intense light in human subjects suggests similar increases in PER2 dependent metabolism, implicating the use of intense light for the treatment of cardiovascular disease. 16PRE30510006 Grant to C.M.B and AHA Postdoctoral Fellowship 19POST34380105 Grant to Y.O. Competing interests: The authors declare there are no conflicts of interest.