Date of Award
Doctor of Philosophy (PhD)
Molecular, Cellular, and Systems Physiology
Jonathan H. Jaggar, Ph.D.
Charles W. Leffler, Ph.D. Rennolds S. Ostrom, Ph.D. Radhakrishna Rao, Ph.D. Christopher M. Waters, Ph.D.
Rationale: Physiological functions of mitochondria in contractile arterial smooth muscle cells are poorly understood. Mitochondria can uptake calcium (Ca2+), but intracellular Ca2+ signals that regulate mitochondrial Ca2+ concentration ([Ca2+]mito) and physiological functions of changes in [Ca2+]mito in arterial smooth muscle cells are unclear.
Objective: 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 smooth muscle cells of resistance–size cerebral arteries.
Methods and Results: Endothelin–1 (ET–1) activated Ca2+ waves and elevated global Ca2+ concentration ([Ca2+]i) via inositol 1,4,5–triphosphate 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 kappa B (NF–κB) p50 subunit and ET–1–induced IP3R–mediated mitoROS elevated NF–κB–dependent transcriptional activity. ET–1 elevated voltage–dependent Ca2+ (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 smooth muscle cells, thereby modulating arterial contractility.
Narayanan, Damodaran , "Mitochondrial Regulation of Arterial Contractility" (2010). Theses and Dissertations (ETD). Paper 177. http://dx.doi.org/10.21007/etd.cghs.2010.0223.