l-Citrulline supplementation during pregnancy improves perinatal and postpartum maternal vascular function in a mouse model of preeclampsia

Abstract

Preeclampsia is a spontaneously occurring pregnancy complication diagnosed by new onset hypertension and end-organ dysfunction with or without proteinuria. This pregnancy-specific syndrome contributes to maternal morbidity and mortality and can have detrimental effects on fetal outcome. Preeclampsia is also linked to increased risk of maternal cardiovascular disease throughout life. Despite intense investigation of this disorder, few treatment options are available. The aim of this study was to investigate the potential therapeutic effects of maternal L-citrulline supplementation on pregnancy-specific vascular dysfunction in the ♀ C57BL/6J x ♂ C57BL/6J C1q-/- preeclampsia-like mouse model. L-citrulline is a non-essential amino acid that is converted to L-arginine to promote smooth muscle and blood vessel relaxation and improve nitric oxide (NO) mediated vascular function. To model a preeclampsia-like pregnancy, female C57BL/6J mice were mated to C1q-/- male mice, and a subset of dams were supplemented with L-citrulline throughout pregnancy. Blood pressure, systemic vascular glycocalyx, and ex-vivo vascular function were investigated in late pregnancy, and postpartum at 6 and 10 months of age. Main findings show that L-citrulline reduced blood pressure, increased vascular glycocalyx volume and rescued ex-vivo vascular function at gestation day 17.5 in this preeclampsia-like model. The vascular benefit of L-citrulline also extended postpartum, with improved vascular function and glycocalyx measures at 6 and 10 months of age. L-citrulline mediated vascular improvements appear, in part, attributable to NO pathway signaling. Taken together, L-citrulline supplementation during pregnancy appears to have beneficial effects on maternal vascular health which may have translational implications for improved maternal cardiovascular health.

Maternal folic acid and vitaminB12supplementation during medium to late gestation promotes fetal development via improving placental antioxidant capacity, angiogenesis and amino acid transport

“…The reduced Cit concentration may indicate that Cit is being utilized for placental and fetal development, which can be beneficial for vascular health. 45,46 Our correlation analysis showed a significant positive relationship between placental vascular density and cord blood amino acid concentration (Fig. S1).…”

l‐Citrulline ameliorates pathophysiology in a rat model of superimposed preeclampsia

“…However, most of them studied the correlation between serum levels of citrulline and preeclampsia, and none of them studied the direct effect of citrulline supplementation in preeclampsia. Only shortly after we had completed this study, a report was published online ahead of print, which demonstrated that citrulline improves perinatal and postpartum maternal vascular function in a preeclampsia‐like genetically modified mouse model (Gemmel et al, 2021). Compatible with our findings, Gemmel et al suggest that citrulline has beneficial effects on maternal vascular health in C1q −/− mice, attributable to NO signalling.…”

Long-Term Impacts of Preeclampsia on the Cardiovascular System of Mother and Offspring

“…In the male C57BL/6J×female C57BL/6J C1q − / − rodent model of preeclampsia, L-citrulline supplementation during pregnancy was shown to improve maternal NO-mediated vascular function at 7 months postpartum via conversion to L-arginine. 36 Booz et al 37 verified that inhibition of AT1-AAs improves the changes in blood pressure, cardiac hypertrophy, and cardiac mitochondrial function in the reduced uterine perfusion pressure rat model of preeclampsia, not only during pregnancy but also at 10 weeks postpartum. Actually, there has been a long history of using angiotensin receptor blockers to selectively block AT1R and treat CVD, similar to treatments for hypertension.…”