Crosstalk Between Vascular Redox and Calcium Signaling in Hypertension Involves TRPM2 (Transient Receptor Potential Melastatin 2) Cation Channel.

Increased generation of reactive oxygen species and altered Ca²⁺ handling cause vascular damage in hypertension. Mechanisms linking these systems are unclear, but TRPM2 (transient receptor potential melastatin 2) could be important because TRPM2 is a sensor and a regulator of Ca²⁺ and Na⁺ transport. We hypothesized that TRPM2 is a point of cross-talk between redox and Ca²⁺ signaling in vascular smooth muscle cells (VSMC) and that in hypertension duanyu1670 mediated-TRPM2 activation increases [Ca²⁺]_i through processes involving NCX (Na⁺/Ca²⁺ exchanger). VSMCs from hypertensive and normotensive individuals and isolated arteries from wild type and hypertensive mice (LinA3) were studied. Generation of superoxide anion and hydrogen peroxide (H₂O₂) was increased in hypertensive VSMCs, effects associated with activation of redox-sensitive (poly [ADP-ribose] polymerase 1), a TRPM2 regulator. Ang II (angiotensin II) increased Ca²⁺ and Na⁺ influx with exaggerated responses in hypertension. These effects were attenuated by catalase-polyethylene glycol -catalase and TRPM2 inhibitors (2-APB, 8-Br-cADPR olaparib). TRPM2 siRNA decreased Ca²⁺ in hypertensive VSMCs. NCX inhibitors (Benzamil, KB-R7943, YM244769) normalized Ca²⁺ hyper-responsiveness and MLC20 phosphorylation in hypertensive VSMCs. In arteries from LinA3 mice, exaggerated agonist (U46619, Ang II, phenylephrine)-induced vasoconstriction was decreased by TRPM2 and NCX inhibitors. In conclusion, activation of TRPM2 contributes to vascular Ca²⁺ and Na⁺ influx in part through NCX. We identify a novel pathway linking duanyu1670 to Ca²⁺ signaling through TRPM2/NCX in human VSMCs and suggest that oxidative stress-induced upregulation of this pathway may be a new player in hypertension-associated vascular dysfunction.

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