Sex‐differences in Mitochondrial Respiration in Rat Cerebral Arteries

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We determined whether sex-differences exist in mitochondrial oxygen consumption rate (OCR) in cerebral arteries from male and female Sprague Dawley rats. The Seahorse XFe24 analyzer was used to explore mitochondrial OCR under basal conditions and after pharmacological challenge using the mitochondria-specific drug, diazoxide (DZ). Western blotting was used to determine levels of mitochondrial and non-mitochondrial proteins. The different components of mitochondrial respiration: including basal respiration (97 ± 15 pM/min/μg protein), ATP production (33 ± 5 pM/min/μg protein), proton leak (64 ± 11 pM/min/μg protein), maximal respiration (147 ± 22 pM/min/μg protein), and spare capacity (50 ± 8 pM/min/μg protein) were significantly elevated (p < 0.05) in female compared with male arteries (36 ± 9 pM/min/μg protein; 15 ± 4 pM/min/μg protein; 21 ± 5 pM/min/μg protein; 63 ± 12 pM/min/μg protein; 26 ± 7 pM/min/μg protein; respectively). Acute treatment with DZ had little effect on OCR of male arteries but decreased ATP production (19 ± 3 pM/min/μg), maximal respiration (78 ± 14 pM/min/μg protein), and spare respiratory capacity (26 ± 9 pM/min/μg protein) in female arteries to near male levels. The mitochondrial Complex proteins, the voltage-dependent anion channel protein, and phosphorylated endothelial and neuronal nitric oxide synthase levels were significantly elevated in female compared with male arteries. Our findings provide evidence for substantial sex-differences in mitochondrial respiratory dynamics in large cerebral arteries and may provide the mechanistic basis for greater adaptability and resistance to injury of the female cerebral vasculature. This work was supported by NIH grants HL-077731, HL-030260, HL-065380, and HL-093554.