Mitochondrial Regulation of Arterial Contractility

<p><strong>Rationale:</strong> 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.</p> <p><strong>Objective:</strong> 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.</p> <p><strong>Methods and Results:</strong> 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⁺ (Ca_V1.2) channel expression, leading to an increase in both pressure (myogenic tone)– and depolarization–induced vasoconstriction. Baseline Ca_V1.2 expression and the ET–1–induced elevation in Ca_V1.2 expression were both reduced by IP₃R inhibition, mitochondrial electron transport chain block, antioxidant treatment, and NF–κB subunit knockdown, leading to vasodilation.</p> <p><strong>Conclusions:</strong> IP₃R–mediated SR Ca²⁺ release elevates [Ca²⁺]_mito, which induces mitoROS generation. MitoROS activate NF–κB, which stimulates Ca_V1.2 channel transcription. Thus, mitochondria sense IP₃R–mediated SR Ca²⁺ release to control NF–κB–dependent Ca_V1.2 channel expression in arterial smooth muscle cells, thereby modulating arterial contractility.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biomedical Sciences

Year dc:date.available

2010

Author dc:creator

• Narayanan, Damodaran

Contributors dc:contributor

• Jonathan H. Jaggar, Ph.D.

• arterial smooth muscle
• calcium signaling
• CaV1.2 expression
• mitochondria
• myogenic tone
• Anatomy
• Cardiovascular System
• Medicine and Health Sciences

Repository record dc:identifier

https://dc.uthsc.edu/dissertations/177

OAI identifier oai:identifier

oai:dc.uthsc.edu:dissertations-1185