P2X7 channel activity in the vascular endothelium inhibits vasodilation and increases blood pressure

High blood pressure, hypertension, is the top risk factor for the leading causes of death, cardiovascular disease and stroke. Blood pressure can be elevated by increasing contractility of resistance-sized arteries. Contractility is increased by depolarization of smooth muscle membrane potential which is regulated by the balance of smooth muscle and endothelial cell resident ion channel activity. P2X7, a non-selective cation channel, is expressed in the endothelium of resistance-sized arteries. We hypothesized that activation of endothelial cell resident P2X7 channels would short-circuit endothelium dependent hyperpolarization and inhibit vasodilation. P2X7 agonists, BzATP and histone proteins, decrease flow-mediated dilation (FMD) when applied directly to the endothelium. Application of an orthosteric P2X7 antagonist, PPADS, increases FMD. Mesenteric resistance-sized arteries from endothelial cell specific P2X7 knockout (P2X7 ecKO) mice have increased FMD, do not constrict to P2X7 agonists during flow, and have decreased histone-induced Ca 2+ influx in en face preparations. This data demonstrates that ecP2X7 activity inhibits vasodilation. To determine if this translates to increased blood pressure, we used tail cuff plethysmography to measure blood pressure in aged P2X7 ecKO and floxed control mice. Aged (9 mth) control animals have elevated blood pressure, consistent with previous reports. P2X7 ecKO mice have decreased blood pressure relative to age-matched floxed control animals, consistent with increased vasodilation in P2X7 ecKO arteries. This data demonstrates that P2X7 activity in the vascular endothelium inhibits vasodilation and increases blood pressure. This may provide new therapeutic strategies to treat hypertension and lessen the burden of cardiovascular disease and stroke. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.