The interplay between reactive oxygen species (ROS) and Ca2?+ plays a major role in the regulation of vascular function. However, mechanisms underlying ROS-induced Ca2+-influx and signalling are not fully established. The transient receptor potential melastatin 2 cation channel (TRPM2) is a redox-sensitive cation channel that promotes influx of Ca2+ after activation by H2O2 through PARP-ADPR-dependent mechanisms in inflammatory cells. TRPM2 also regulates Na+ influx and by increasing intracellular Na+ content, it could interfere with the function of the Na+-Ca2+ exchanger (NCX), which may confer a novel mechanism whereby ROS influences Ca2+ influx and signalling. Here, we postulated that redox-sensitive Ca2+ regulation involves TRPM2 and NCX; a process exacerbated in hypertension leading to vascular dysfunction. We also interrogated the role of Nox4 in these processes. Mesenteric arteries from wild-type (WT), LinA3 (chronic Ang II-induced mouse model of hypertension), Nox4-/-, and LinA3/Nox4-/- and VSMCs cultures from human arteries were used. Vascular function, assessed by wire myography, demonstrated that mesenteric arteries from LinA3 mice present increased Phe-induced vasoconstriction (Emax – LinA3 vs WT: 9.37±0.51 vs 6.79±0.29); an effect ameliorated by olaparib (PARP inhibitor) and 2-APB (TRPM2 blocker). The mRNA expression of NOX4 (fold change: 3.05±0.30), TRPM2 (fold change: 1.38±0.24), and NCX exchanger (fold change: 1.97±0.34) were increased in LinA3 mice; an effect not observed in LinA3/Nox4-/- mice (a model with reduced H2O2 levels). Ang II stimulation increased Ca2+ influx in human VSMC from normotensive (AUC-Ex490/Em535: 15400±917.5) and hypertensive subjects (AUC-Ex490/Em535: 22460±2388). TRPM2 activation inhibitors, such as 2-APB, olaparib and 8-Br, as well as, NCX inhibitors benzamil, KB-R7943 and YM244769, ameliorated Ang II-induced Ca2+ influx in human VSMC. In conclusion, TRPM2/NCX-induced increase in intracellular levels of calcium may be involved in hypertension-associated vascular dysfunction. Our data also suggests that oxidative stress regulates Ca2+ homeostasis through TRPM2-dependent mechanisms.