Mitochondria control functional CaV1.2 expression in smooth muscle cells of cerebral arteries

Abstract

Rationale: Physiological functions of mitochondria in contractile arterial myocytes are poorly understood. Mitochondria can uptake calcium (Ca 2+), but intracellular Ca2+ signals that regulate mitochondrial Ca2+ concentration ([Ca2+]mito) and Physiological functions of changes in [Ca2+]mito in arterial myocytes are unclear. Objective: To identify Ca2+ signals that regulate [Ca2+]mito, examine the significance of changes in [Ca2+]mito, and test the hypothesis that [Ca2+]mito controls functional ion channel transcription in myocytes of resistance-size cerebral arteries. Methods and Results: Endothelin (ET)-1 activated Ca2+ waves and elevated global Ca 2+ concentration ([Ca2+]i) via inositol 1,4,5-trisphosphate receptor (IP3R) activation. IP3R-mediated sarcoplasmic reticulum (SR) Ca2+ release increased [Ca2+] mito and induced mitochondrial depolarization, which stimulated mitochondrial reactive oxygen species (mitoROS) generation that elevated cytosolic ROS. In contrast, a global [Ca2+]i elevation did not alter [Ca2+]mito, mitochondrial potential, or mitoROS generation. ET-1 stimulated nuclear translocation of nuclear factor (NF)-κB p50 subunit and ET-1-induced IP3R-mediated mitoROS elevated NF-κB-dependent transcriptional activity. ET-1 elevated voltage-dependent Ca (CaV1.2) channel expression, leading to an increase in both pressure (myogenic tone)-and depolarization-induced vasoconstriction. Baseline CaV1.2 expression and the ET-1-induced elevation in CaV1.2 expression were both reduced by IP3R inhibition, mitochondrial electron transport chain block, antioxidant treatment, and NF-κB subunit knockdown, leading to vasodilation. Conclusions: IP3R-mediated SR Ca2+ release elevates [Ca2+]mito, which induces mitoROS generation. MitoROS activate NF-κB, which stimulates CaV1.2 channel transcription. Thus, mitochondria sense IP3R-mediated SR Ca2+ release to control NF-κB-dependent CaV1.2 channel expression in arterial myocytes, thereby modulating arterial contractility. © 2010 American Heart Association, Inc.