Coronary no-reflow, which impacts roughly half of patients following artery reopening for myocardial infarction, remains a major clinical challenge. Here we demonstrate that the incretin GLP-1 (glucagon-like peptide 1) can be used to protect the heart after ischemia by activating ATP-gated K+ channels on pericytes that constrict coronary capillaries. The mechanism involves vagal signaling from gut GLP-1 release triggered by skeletal muscle ischemia, establishing a brain-gut-heart signalling axis. These findings offer potential therapeutic approaches to enhance post-infarction outcomes by targeting pericyte-mediated coronary capillary constriction.