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

Abstract

Background and Purpose Preeclampsia, characterized by hypertension, proteinuria and restriction of fetal growth, is one of the leading causes of maternal and perinatal mortality. So far, there is no effective pharmacological therapy for preeclampsia. The present study was conducted to investigate the effects of supplementation with l‐citrulline in Dahl salt‐sensitive rats, a model of superimposed preeclampsia. Experimental Approach Parental Dahl salt‐sensitive rats were treated with l‐citrulline (2.5 g·L−1 in drinking water) from the day of mating to the end of lactation period. Blood pressure was monitored throughout pregnancy and markers of preeclampsia were assessed. Endothelial function of the pregnant Dahl salt‐sensitive rats was assessed by wire myograph. Key Results In Dahl salt‐sensitive rats, l‐citrulline supplementation significantly reduced maternal blood pressure, proteinuria and levels of circulating soluble fms‐like tyrosine kinase 1. l‐Citrulline improved maternal endothelial function by augmenting the production of nitric oxide in the aorta and improving endothelium‐derived hyperpolarizing factor‐mediated vasorelaxation in resistance arteries. l‐Citrulline supplementation improved placental insufficiency and fetal growth, which were associated with an enhancement of angiogenesis and reduction of fibrosis and senescence in the placentas. In addition, l‐citrulline down‐regulated genes involved in the TLR4 and NF‐κB signalling pathways. Conclusion and Implications This study shows that l‐citrulline supplementation reduced gestational hypertension and improved placentation and fetal growth in a rat model of superimposed preeclampsia. l‐Citrulline supplementation may provide an effective and safe therapeutic strategy for preeclampsia that benefits both the mother and the fetus.

L-Citrulline Supplementation Reduces Blood Pressure and Myocardial Infarct Size under Chronic Intermittent Hypoxia, a Major Feature of Sleep Apnea Syndrome

“…Our results are in line with previous studies demonstrating citrulline efficiency against hypertension in different animal models. The 0.25% of citrulline given in drinking water during 8 weeks decreased MBP in spontaneously hypertensive rats [ 35 ] and dahl salt-sensitive rats [ 52 ]. Here, we demonstrated that, in normotensive rats, citrulline prevents MBP increase induced by IH.…”

“…This could be explained by a decrease in eNOS activity triggered by ADMA production and/or by a decrease in arginine availability due to an increase in arginase activity as previously described under IH [ 30 , 63 ]. Regarding citrulline protective mechanisms, it was demonstrated to impact eNOS dynamics by increasing the total eNOS protein expression, S1177 phosphorylation, and NO production [ 52 , 64 ]. However, in the small pulmonary arteries of piglets, the vasorelaxation induced by citrulline was maintained in the presence of N(G)-Nitro-L-arginine methyl ester (L-NAME), this indicates that other factors than eNOS can explain the beneficial impact of citrulline on vascular tone [ 52 ].…”

“…Regarding citrulline protective mechanisms, it was demonstrated to impact eNOS dynamics by increasing the total eNOS protein expression, S1177 phosphorylation, and NO production [ 52 , 64 ]. However, in the small pulmonary arteries of piglets, the vasorelaxation induced by citrulline was maintained in the presence of N(G)-Nitro-L-arginine methyl ester (L-NAME), this indicates that other factors than eNOS can explain the beneficial impact of citrulline on vascular tone [ 52 ]. This could explain why after 2 weeks of IH, citrulline decreased MBP without affecting the eNOS dynamics.…”

Citrulline inhibits LPS‐induced pyroptosis of RAW264.7 macrophages through NF‐κB signaling pathway

“…For example, Man et al have revealed that citrulline attenuates the progression of pre‐eclampsia by suppressing the NF‐κB pathway. 33 In addition, Ba et al have identified that citrulline inhibits ferroptosis in the thymus via inactivating the NF‐κB pathway. 34 Herein, we predicted that citrulline could combine with p65.…”

“…The NF‐κB pathway may be the underlying mechanism of citrulline function. For example, Man et al have revealed that citrulline attenuates the progression of pre‐eclampsia by suppressing the NF‐κB pathway 33 . In addition, Ba et al have identified that citrulline inhibits ferroptosis in the thymus via inactivating the NF‐κB pathway 34 .…”