Maternal citrulline supplementation enhances placental function and fetal growth in a rat model of IUGR: involvement of insulin-like growth factor 2 and angiogenic factors

Abstract

Objective: To determine the effects of maternal citrulline supplementation on fetal growth and placental efficiency in a rat model of intrauterine growth restriction (IUGR) induced by maternal protein restriction.

Methods: Pregnant Sprague–Dawley rats were randomly assigned to three groups: NP (receiving a control 20% protein diet), LP (a 4% protein diet), or LP-CIT (an LP diet along with L-citrulline, 2 g/kg/d in drinking water). On the 15th and 21st day of gestation (GD15 and GD21, respectively), dams underwent a C-section, by which fetuses and placentas were extracted. The expression of genes involved in placental growth and angiogenesis was studied by quantitative RT-PCR.

Results: Maternal citrulline supplementation increased fetal weight at GD21, and fetal weight/placental weight ratio, an index of placental efficiency, from mid gestation (p < 0.001). The expression of Igf2-P0, a placenta-specific variant of insulin-like growth factor 2 (Igf2) gene, and Vegf and Flt-1, involved in angiogenic pathways, was enhanced in the LP-CIT group (versus NP, p < 0.001, p < 0.01, and p < 0.05 for Igf2-P0, Vegf, and Flt-1, respectively).

Conclusions: In a model of IUGR induced by protein deprivation, citrulline enhances fetal growth, placental efficiency, and the expression of genes involved in angiogenesis. The relevance of such effect in human pregnancies complicated by IUGR warrants further study.

Keywords:

• Amino acids
• angiogenesis
• growth factor
• placenta
• transporter

Acknowledgements

We thank Guillaume Poupeau and Vincent Dochez for their help with surgical procedures, Myriam Robard and her technicians for their staining procedure of placentas.

N.-T.T., A.B., N.W. and D.D. designed the research; N.-T.T., A.B., V.A., E.M. and I.G. conducted the experiments; N.-T.T., V.A. and D.D. wrote the article; N.W. and D.D. had primary responsibility for final content. All authors read and approved the final manuscript.

Declaration of interest

None of the authors had any conflict of interest. N-T.T. received fellowship grants from SFNEP (French Society for Clinical Nutrition and Metabolism), Nestlé-SFP (French Society of Pediatrics), and SanTDige Foundation. This research was funded, in part, by a 3ARP prize from Ajinomoto (to D.D.).

Supplementary material available online