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Title: Dietary L-arginine supplementation during mouse gestation enhances reproductive performance and Vegfr2 transcription activity in the fetoplacental unit

item GREENE, J - Mississippi State University
item DUNAWAY, C - Mississippi State University
item BOWERS, S - Mississippi State University
item RUDE, B - Mississippi State University
item FEUGANG, J - Mississippi State University
item RYAN, PETER - Mississippi State University

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/29/2011
Publication Date: 1/25/2012
Citation: Greene, J.M., Dunaway, C.M., Bowers, S.D., Rude, B.J., Feugang, J.M., Ryan, P. 2012. Dietary L-arginine supplementation during mouse gestation enhances reproductive performance and Vegfr2 transcription activity in the fetoplacental unit. Journal of Nutrition. 142(3):456-460.

Interpretive Summary: Amino acids are the building blocks for proteins, which are the functional units within living cells. In addition to serving a role in protein synthesis, amino acids can also have functional roles within cells, as they are broken down into molecules which serve a role in various cellular processes. L-arginine is an amino acid that is known to have variety of functions because it serves as a precursor for many bio-active molecules. One of these bioactive molecules is nitric oxide, which has vasoactive properties, i.e. it exerts an influence on blood vessels throughout the body. The objective of this study was to investigate whether dietary L-arginine supplementation influences the reproductive performance in mice and whether any beneficial effects are manifested at the level of the fetus and placenta by way of increased vascular development. To this end, female mice were bred to genetically engineered male mice that expressed a photonic reporter gene coupled with the gene associated with the production of the protein vascular endothelial growth factor receptor 2 (Vegfr2), which is extremely important for vascular development during pregnancy. When the Vegfr2 gene is switched on, the photonic gene produces light, which can be monitored and quantified using highly sensitive light-detecting cameras, providing a non-invasive method of monitoring Vegfr2 gene activation. Pregnant females were separated into two groups, one that received a diet supplemented with L-arginine and one that received a diet supplemented with L-alanine which served as an isonitrogenous control. Pregnant mice were imaged daily from day 12 to day 18 of pregnancy to detect Vegfr2 gene expression. Dietary L-arginine supplementation increased the number of pups born alive and the number sites on the uterus where embryo implantation occurs. This would suggest that L-arginine has a postive effect during the critical time of embryo implantation which lead to more pups being born. Additionally, L-arginine supplementation resulted in increased and an earlier rise in Vegfr2 gene activation, indicating a positive influence of vascular development during pregnancy. Overall, these findings suggest that L-arginine has the potential to improve the reproductive performance of litter bearing animals, and this improvement is associated with mechanisms that have a positive influence on vascular development of the fetus and placenta.

Technical Abstract: Regarded as one of the most versatile amino acids, arginine serves as a precursor for many molecules and has been reported to improve the reproductive performance of rats and pigs. To this end, we sought to determine if dietary L-arginine alters fetoplacental vascular endothelial growth factor receptor-2 (Vegfr2) transcription activity. Eighteen wild-type FVB/N female mice were bred to homozygous FVB/N-Tg(Vegfr2-luc)-Xen male mice. Bred female mice received 1 of 2 experimental diets: one supplemented with 2.00% (wt:wt) L-arginine (+Arg) or 1 supplemented with 4.10% (wt:wt) alanine (+Ala) to serve as an isonitrogenous control for +Arg. In addition, 6 mice were fed a non-supplemented control (Con) diet to normalize bioluminescent imaging data. All data were analyzed using ANOVA followed by Fisher’s least significant difference. Total feed intake did not differ between groups; however, mice in the +Arg group consumed more arginine (P < 0.05). Arginine supplementation increased weight gain during the latter one-third of gestation (d 12– 18), total litter size, number of pups born alive, number of placental attachment sites, litter birth weight, and litter weight of pups born alive but decreased the individual birth weights (P < 0.05). During d 12–18, arginine supplementation increased (P <0.05) the mean total Vegfr2 transcription activity and Vegfr2 transcription activity corrected for fetoplacental mass. Moreover, mice in the +Arg group had an earlier rise in Vegfr2 transcription activity. In conclusion, our results demonstrate that the beneficial effect of dietary L-arginine supplementation on mammalian reproduction is associated with enhanced Vegfr2 transcription activity in fetoplacental tissues.