Article Text

Download PDFPDF

159 Trpm2 ion channel activation contributes to redox-sensitive vascular dysfunction in hypertension
  1. Rheure Alves-Lopes,
  2. Augusto C Montezano,
  3. Karla B Neves,
  4. Aikaterini Anagnostopoulou,
  5. Silvia Lacchini,
  6. Rhian M Touyz
  1. University of Glasgow.


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.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.