A relative L-arginine deficiency contributes to endothelial dysfunction across the stages of the menopausal transition

Figures

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  Figure 1. Plasma levels of (A) L‐arginine and (B) citrulline in premenopausal (pre), early and late perimenopausal (peri), and early and late postmenopausal (post) women. Data are presented as mean ± SE. Significance levels: *P < 0.05 versus early and late perimenopausal women.

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  Figure 2. Plasma levels of ornithine in premenopausal (pre), and early and late postmenopausal (post) women. Data are presented as mean ± SE. Significance levels: *P < 0.05 versus premenopausal women.

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  Figure 3. Plasma levels of (A) L‐NMMA, (B) ADMA and (C) SDMA in premenopausal (pre), early and late perimenopausal (peri), and early and late postmenopausal (post) women. Data are Median‐interquartile range and outliers are included at the 5th/95th percentile. Significance levels: *P < 0.0001 versus premenopausal and early and late perimenopausal women.

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  Figure 4. L‐arginine/L‐NMMA ratio, a measure of L‐arginine availability, in premenopausal (pre), early and late perimenopausal (peri), and early and late postmenopausal (post) women. Data are log transformed and are presented as mean ± SE. Significance levels: *P < 0.0001 versus premenopausal and early and late perimenopausal women.

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  Figure 5. Brachial artery FMD was inversely related to (A) plasma L‐NMMA, and positively related to (B) L‐arginine/L‐NMMA ratio.

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  Figure 6. Scheme depicting how altered L‐arginine metabolism may contribute to endothelial dysfunction in postmenopausal women. In postmenopausal women, a relative L‐arginine deficiency may occur because of a greater metabolism of L‐arginine to ornithine due to increased arginase, and/or increased L‐arginine methylation to NG‐monomethyl‐l‐arginine (L‐NMMA). The elevated L‐NMMA would compete with L‐arginine for endothelial nitric oxide synthase (eNOS) binding sites. Elevated ornithine and L‐NMMA would also compete with L‐arginine for intracellular transport. A relative L‐arginine deficiency would uncouple eNOS, resulting in elevated superoxide (O2 −) production and reduced NO. The O2 − would react with nitric oxide (NO), further reducing NO bioavailablity. Superoxide and other reactive oxygen species (ROS) could impair the activity of dimethylarginine dimethylaminohydrolase (DDAH) and increase L‐NMMA. BH 4, tetrahydrobiopterin; O2, oxygen; ASS=argininosuccinate synthase; ASL, argininosuccinate lyase; PRMT, protein arginine methyltransferase; OTC, ornithine carbamoyltransferase.