![]() 17 Recently, others have shown that TRPM8 exists in both the cytomembrane and sarcoplasmic reticulum (SR) of pulmonary arterial smooth muscle cells. Our previous study demonstrates that the activation of vascular TRPM8 by menthol has a favorable antihypertensive effect through inhibition of the RhoA/Rho kinase pathway. 12 The transient receptor potential melastatin 8 (TRPM8) channel is a mild cold‐sensing nonselective cation channel that can be activated by its specific agonist, menthol. 16 Using mitochondria‐targeted antioxidants to alleviate mitochondrial oxidative stress might efficiently attenuate hypertension. 15 It is worth investigating whether ameliorating mitochondrial dysfunction disrupts this vicious cycle and attenuates vascular dysfunction in hypertension.Ĭurrently, application of ROS scavengers, which eliminate the total levels of tissue and cellular ROS, has not generally achieved favorable effects on ameliorating cardiovascular diseases. Indeed, ROS‐mediated upregulation of the RhoA/Rho kinase pathway promotes vasoconstriction and contributes to high blood pressure (BP). 14 This vicious cycle might be an important factor contributing to the excess mitochondrial ROS production in VSMCs. 13 Under pathological conditions of cytosolic Ca 2+ overload, mitochondria are capable of taking up large amounts of Ca 2+. 12 Ang II–induced mitochondrial ROS generation promotes Ca 2+ influx and, subsequently, contraction in arterial smooth muscle. 11 Excessive mitochondrial ROS is implicated in the development of vascular dysfunction. 10 Meanwhile, mitochondrial matrix Ca 2+ overload impairs mitochondrial function and leads to ROS generation. 9 PDH is one of the key dehydrogenases of the tricarboxylic acid cycle, the activity of which is blunted by Angiotensin II (Ang II) by increasing PDH phosphorylation in vascular smooth muscle cells (VSMCs). 8 Increased physiological levels of mitochondrial Ca 2+ uptake is the coordinated upregulation of the entire oxidative phosphorylation activity. Pyruvate dehydrogenase (PDH) and several complexes of electron transport have been reported to be Ca 2+ dependent. Mitochondria, Ca 2+, and reactive oxygen species (ROS) are each integral to vascular function and are thought to be involved in the development of hypertension. 3, 4, 5, 6, 7 Although antagonism of the renin‐angiotensin‐aldosterone system was recommended to improve CIH, how to prevent CIH through nonpharmaceutical therapy in the general population remains unknown. Among them, the overdrive of renin‐angiotensin‐aldosterone system plays a crucial role in the development of CIH. 1, 2 The pathogenesis of cold‐induced hypertension (CIH) involves the activation of the sympathetic nervous system, the renin‐angiotensin‐aldosterone system, and the inflammatory process. The prevalence of hypertension and related cardiovascular diseases is higher in people who live in colder areas or during colder months. ![]() Noxious cold temperature is a nonmodifiable risk factor for hypertension. These effects of menthol were further validated in angiotensin II–induced hypertensive mice. The activation of TRPM8 by dietary menthol inhibited vascular reactive oxygen species generation, vasoconstriction, and lowered blood pressure through attenuating excessive mitochondrial reactive oxygen species mediated the activation of RhoA/Rho kinase in a TRPM8‐dependent manner. In vivo, long‐term noxious cold stimulation dramatically increased vasoconstriction and blood pressure. TRPM8 activation by menthol antagonized angiotensin II induced mitochondrial respiratory dysfunction and excess reactive oxygen species generation by preserving pyruvate dehydrogenase activity, which hindered reactive oxygen species–triggered Ca 2+ influx and the activation of RhoA/Rho kinase pathway. ![]() In vitro, we confirmed that sarcoplasmic reticulum–resident TRPM8 participated in the regulation of cellular and mitochondrial Ca 2+ homeostasis in the vascular smooth muscle cells. Primary vascular smooth muscle cells from wild‐type or Trpm8 −/− mice were cultured.
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