Transient receptor potential melastatin 7 (TRPM7) cation channel is a unique protein that has the dual ability to act as a channel to regulate transmembrane Mg2+ transport and also as a kinase to promote cellular signaling. Despite increasing awareness of the importance of Mg2+ in cardiovascular biology nothing is known about TRPM7 and its kinase domain in the pathophysiology of hypertension. We previously demonstrated that Ang II regulates TRPM7 invitro. Here we studied TRPM7 kinase-deficient mice to explore the role of the TRPM7 kinase domain in Ang II-induced hypertension. TRPM7 kinase deficient mice (TRPM7+/-) and wild type (WT) counterparts were infused with Ang II (400 ng/kg/min; minipumps) for 4 weeks. Blood pressure (BP) was measured by tail cuff. Vascular reactivity and structure studies were performed by myography in mesenteric arteries. Although baseline BP tended to be higher in TRPM7+/- versus WT mice (127 ± 6.0 vs 119 ± 2.2 mmHg), significance was not achieved. TRPM7+/- mice displayed earlier onset of BP increase by Ang II (2 weeks; WT-Ang II: 145 ± 5 vs TRPM7+/-Ang II: 178 ± 9; mmHg). After 4 weeks, BP was significantly higher in TRPM7+/- (174 ± 10 mmHg) than in WT mice (147 ± 8 mmHg). Ang II-induced hypertension was associated with cardiac hypertrophy, an effect that was exaggerated in TRPM7+/- mice (WT: 4.4 ± 0.1; WT-Ang II: 5.0 ± 0.2; TRPM7+/-: 4.5 ± 0.1; TRPM7+/-Ang II: 5.7 ± 0.1 g/body weight). Mesenteric arteries from Ang II-infused TRPM7+/- mice exhibited decreased sensitivity to acetylcholine (pD2; WT-Ang II: 7.6 ± 0.3 vs. TRPM7+/-Ang II: 6.7 ± 0.4), and reduced maximal relaxation compared to WT mice (WT-Ang II: 88 ± 8% vs TRPM7+/-Ang II: 59 ± 10%). Ang II induced a leftward shift in the stress-strain relationship for both WT and TRPM7+/- mice in a similar fashion. Plasma analysis revealed that TRPM7+/- mice were hypomagnesemic, and that Ang II increased Mg2+ levels to a greater extent in WT than in TRPM7+/- mice (WT: 0.65 ± 0.02; WT-Ang II: 0.74 ± 0.04; TRPM7+/-: 0.60 ± 0.01; TRPM7+/-Ang II: 0.64 ± 0.02; mmol/L). In conclusion, our findings demonstrate that hypertension, cardiac hypertrophy and endothelial dysfunction are exaggerated by Ang II in TRPM7+/- hypomagnesemic mice, suggesting a novel role for TRPM7 kinase domain in cardiovascular pathophysiology.