Pericytes contract during acute myocardial infarction (AMI) resulting in capillary constriction, which further contributes to the ischemic damage and enlargement of infarct size. We hypothesized that increased intramyocardial pressure during ischemia can be sensed by mechanosensitive Transient Receptor Potential (TRP) channels in cardiac pericytes, resulting in their contraction and worsening of myocardial necrosis during AMI. Here, we show that cultured primary cardiac pericytes express several TRP channels. Live-cell confocal imaging demonstrates that pharmacological stimulation with specific TRPM4 and TRPM7 agonists mobilizes cytosolic Ca(2+) within pericytes. Pressure stimulation (increased compressive forces) also increases pericyte Ca(2+), which is abolished by specific TRPM4 and TRPM7 inhibitors. Lastly, we demonstrate that TRPM4 inhibition in vivo reduces infarct size by 3.5-fold in a rodent AMI model. We conclude that pericytes sense increased compressive forces (pressure) via TRPM channels both in vitro and in vivo. Inhibiting TRP channels may offer a therapeutic option to reduce infarct size in patients experiencing AMI.