CCCP induces vasorelaxation by a mechanism that does not involve K channel activation in smooth muscle cells of arteries.

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H ypertension is one of the most common worldwide diseases and is a major risk factor for a variety of cardiovascular and renal events, including myocardial infarction, stroke, heart failure, and end-stage renal disease. 1 The latest survey shows that hypertension accounts for 7% of global disability adjusted life years and 9.4 million deaths in 2010.2 Therefore, the molecular mechanisms underlying hypertension and the antihypertensive therapies have always been the topics in cardiovascular fields.Mitochondria are dynamic organelles and change their morphology through fission and fusion processes named as mitochondrial dynamics.3 Defects in mitochondrial dynamics are implicated in multiple cardiovascular diseases, for instance, the increased mitochondrial fission contributes to the impairment of endothelial function in diabetes mellitus and the hyperproliferation of pulmonary artery smooth muscle cells in pulmonary arterial hypertension. 4,5 More interestingly, Hong et al 6 show that mitochondrial fission is crucial for O 2 -induced ductus arteriosus constriction and closure at birth in human and rabbits. By using novel digital image processing/single particle tracking techniques, Giedt et al 7 show that mitochondria in endothelial cells continuously undergo fusion/fission, indicating that the onset of biological function related to mitochondrial dynamics should be prompt without needing the transcription and translation processes of mitochondrial dynamic-related proteins. Therefore, we speculate that interfering mitochondrial dynamics could show acute effects on the vascular function. In the present work, we investigate the effects of acute inhibition of mitochondrial fission on the constriction and relaxation of arteries and the underlying mechanisms. We find for the first time that mitochondrial fission of smooth muscle cells is involved in artery constriction, revealing a novel mechanism for vasoconstriction and providing a potential therapeutic target for hypertension. Abstract-Mitochondria

Background/Aims: Endothelin-1 is implicated in the pathogenesis of hypertension, but the underlying mechanisms remained elusive. Our previous study found that inhibition of mitochondrial fission of smooth muscle cells suppressed phenylephrine- and high K⁺-induced artery constriction. Here, we studied the effects of mitochondrial fission inhibitors on endothelin-1-induced vasoconstriction. Methods: The tension of rat mesenteric arteries and thoracic aorta was measured by using a multi-wire myograph system. Mitochondrial morphology of aortic smooth muscle cells was observed by using transmission electron microscopy. Results: Dynamin-related protein-1 selective inhibitor mdivi-1 relaxed endothelin-1-induced constriction, and mdivi-1 pre-treatment prevented endothelin-1-induced constriction of rat mesenteric arteries with intact and denuded endothelium. Mdivi-1 had a similar inhibitory effect on rat thoracic aorta. Another mitochondrial fission inhibitor dynasore showed similar effects as mdivi-1 in rat mesenteric arteries. Mdivi-1 inhibited endothelin-1-induced increase of mitochondrial fission in smooth muscle cells of rat aorta. Rho-associated protein kinase inhibitor Y-27632 which relaxed endothelin-1-induced vasoconstriction inhibited endothelin-1-induced mitochondrial fission in smooth muscle cells of rat aorta. Conclusion: Endothelin-1 increases mitochondrial fission in vascular smooth muscle cells, and mitochondrial fission inhibitors suppress endothelin-1-induced vasoconstriction.