The L-NAME mouse model of preeclampsia and impact to long-term maternal cardiovascular health

Abstract

Preeclampsia affects ∼2–8% of pregnancies worldwide. It is associated with increased long-term maternal cardiovascular disease risk. This study assesses the effect of the vasoconstrictor N(ω)-nitro-L-arginine methyl ester (L-NAME) in modelling preeclampsia in mice, and its long-term effects on maternal cardiovascular health. In this study, we found that L-NAME administration mimicked key characteristics of preeclampsia, including elevated blood pressure, impaired fetal and placental growth, and increased circulating endothelin-1 (vasoconstrictor), soluble fms-like tyrosine kinase-1 (anti-angiogenic factor), and C-reactive protein (inflammatory marker). Post-delivery, mice that received L-NAME in pregnancy recovered, with no discernible changes in measured cardiovascular indices at 1-, 2-, and 4-wk post-delivery, compared with matched controls. At 10-wk post-delivery, arteries collected from the L-NAME mice constricted significantly more to phenylephrine than controls. In addition, these mice had increased kidney Mmp9:Timp1 and heart Tnf mRNA expression, indicating increased inflammation. These findings suggest that though administration of L-NAME in mice certainly models key characteristics of preeclampsia during pregnancy, it does not appear to model the adverse increase in cardiovascular disease risk seen in individuals after preeclampsia.

Unaltered Long-Term Maternal Endothelin System in a Gestational Hypertensive Rat Model

“…These findings were supported by a recent study reporting that the MAP of the mice receiving L-NAME during pregnancy returned to normal levels after discontinuation of treatment at 1 week postpartum, and this level was maintained up to 10 weeks postpartum, as was the case with the circulating ET-1 levels. 20 However, these findings were opposite to the findings in human studies, in which they had proven that there was persistent endothelial dysfunction with hypertension and an increase in inflammatory biomarkers up to more than 20 years postpartum. 28,29 They believed that persistent endothelial dysfunction in at-risk women was due to lowgrade chronic inflammation.…”

“…This model did not appear to show adverse effects on long-term cardiovascular risk after insult by preeclampsia because all preeclamptic cardiovascular indices, including circulating ET-1 levels, were resolved by 10 weeks postpartum. 20 Another animal model of preeclampsia was used, using the RUPP technique, and the results showed that impaired vascular function persisted at three months postpartum in both the mesenteric and aortic vessels, suggesting that the vasculature did not fully recover from the insult of preeclampsia and remained at increased risk for cardiovascular diseases in later life. 21 There was a human study that found a NO/ET-1 imbalance, suggesting that endothelial dysfunction rather than BP normalisation persisted for up to three months postpartum and possibly accounted for the increased CVD risk in women with a history of HDPs.…”

Adrenomedullin has a pivotal role in trophoblast differentiation: A promising nanotechnology-based therapeutic target for early-onset preeclampsia

“…A wide range of PE models, including the spontaneous PE model, nitric oxide synthase inhibition model, angiogenesis factor imbalance model, oxygen stress model, immune response model, and vascular injury model have been developed to study the complex pathogenesis and symptoms of PE. In this study, l -NAME was used to induce EOPE-like phenotypes, which are highly similar to the clinical manifestations, pathological changes, oxidative stress, and inflammatory responses of EOPE ( 55 ). We acknowledge that it is unlikely that one model alone would be able to cover all aspects of EOPE pathogenesis.…”

“…We acknowledge that it is unlikely that one model alone would be able to cover all aspects of EOPE pathogenesis. However, the l -NAME model is relatively simple and more accessible and allows time-dependent monitoring of changes in placenta, vasculature, and kidney during pregnancy ( 55 ). This model has also been used to study the therapeutic potential of various compounds.…”

Neurodevelopmental Disruptions in Children of Preeclamptic Mothers: Pathophysiological Mechanisms and Consequences

“…Despite this, an increase in VEGF has been observed in PE-F1 mice, which could occur to compensate for the reduced levels of PGF [37]. A well-established and commonly employed method for inducing PE in mothers is through the administration of NG-nitro-L-arginine methyl ester (L-NAME) [90][91][92]. Research from our laboratory evaluated the effect of L-NAME-induced PE on offspring at an ontogenetic stage equivalent to childhood through the cerebellar expression of VEGF and two of its receptors, pY951 VEGF R2 and pY1172 VEGF R2.…”