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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.

SUBMITTER: de Alwis N

PROVIDER: S-EPMC9356384 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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

de Alwis Natasha N Binder Natalie K NK Beard Sally S Mangwiro Yeukai Tm YT Kadife Elif E Cuffe James Sm JS Keenan Emerson E Fato Bianca R BR Kaitu'u-Lino Tu'uhevaha J TJ Brownfoot Fiona C FC Marshall Sarah A SA Hannan Natalie J NJ

Life science alliance 20220805 12

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 ...[more]

PMID: 36260752

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Project description:IntroductionTo investigate the mechanism underlying the increased risk of subsequent neurodevelopmental disorders in children born to mothers with preeclampsia, we evaluated the neurodevelopment of offspring of a preeclampsia rat model induced by the administration of N-nitro-L-arginine methyl ester (L-NAME) and identified unique protein signatures in the offspring cerebrospinal fluid.MethodsPregnant rats received an intraperitoneal injection of L-NAME (250 mg/kg/day) during gestational days 15-20 to establish a preeclampsia model. Behavioral experiments (negative geotaxis, open-field, rotarod treadmill, and active avoidance tests), immunohistochemistry [anti-neuronal nuclei (NeuN) staining in the hippocampal dentate gyrus and cerebral cortex on postnatal day 70], and proteome analysis of the cerebrospinal fluid on postnatal day 5 were performed on male offspring.ResultsOffspring of the preeclampsia dam exhibited increased growth restriction at birth (52.5%), but showed postnatal catch-up growth on postnatal day 14. Several behavioral abnormalities including motor development and vestibular function (negative geotaxis test: p < 0.01) in the neonatal period; motor coordination and learning skills (rotarod treadmill test: p = 0.01); and memory skills (active avoidance test: p < 0.01) in the juvenile period were observed. NeuN-positive cells in preeclampsia rats were significantly reduced in both the hippocampal dentate gyrus and cerebral cortex (p < 0.01, p < 0.01, respectively). Among the 1270 proteins in the cerebrospinal fluid identified using liquid chromatography-tandem mass spectrometry, 32 were differentially expressed. Principal component analysis showed that most cerebrospinal fluid samples achieved clear separation between preeclampsia and control rats. Pathway analysis revealed that differentially expressed proteins were associated with endoplasmic reticulum translocation, Rab proteins, and ribosomal proteins, which are involved in various nervous system disorders including autism spectrum disorders, schizophrenia, and Alzheimer's disease.ConclusionThe offspring of the L-NAME-induced preeclampsia model rats exhibited key features of neurodevelopmental abnormalities on behavioral and pathological examinations similar to humans. We found altered cerebrospinal fluid protein profiling in this preeclampsia rat, and the unique protein signatures related to endoplasmic reticulum translocation, Rab proteins, and ribosomal proteins may be associated with subsequent adverse neurodevelopment in the offspring.

Project description:BackgroundPreeclampsia (PE), a hypertensive disorder of pregnancy affects 2-8% of women and is associated with increased cardiovascular disease (CVD) risk later in life. There is little information about the knowledge of obstetrician-gynecologists in German outpatient care setting regarding the future health risk of PE and knowledge of the current guidelines on treatment and counseling patients post PE. This study aimed to assess whether obstetrician-gynecologists are aware of PE's association with maternal long-term adverse outcomes and providing appropriate counseling.MethodsA random sample of 500 obstetrician-gynecologists in the federal state of Lower Saxony was mailed a survey and a reminder with a second copy of the survey. The questionnaire elicited both personal information, and knowledge on future disease risks, e.g. cardiovascular disease (CVD) and current guidelines as well as on counseling practice. Descriptive analysis was used to analyze the responses.ResultsA total of 212 obstetrician-gynecologists (42.4%) responded to the questionnaire. A large proportion of physicians stated that PE was associated with a higher risk for the development for hypertension (86.6%), stroke (78.5%) and kidney disease (78.0%). Of the participants 75.8% reported that women after PE have a shorter life expectancy. Respondents with knowledge of the current guidelines of the German Association of Obstetrics and Gynecology concerning follow up and risk management of PE (45.2%) were more often aware of the development of CVD and stroke and counseled patients on self -blood-pressure measurement, meaning and long-term-risks of PE and attached importance to family history of PE compared to physicians with no knowledge of the guidelines.ConclusionAlthough the majority of obstetrician-gynecologists were aware of higher CVD risk after PE, weaknesses exist in the follow up care and counseling of these patients. These deficiencies would be amendable to directed educational activities to improve the implementation of current guidelines.

Project description:ImportanceThe association of socioeconomic status and cardiovascular outcomes has been well described, but little is known about whether longitudinal changes in wealth are associated with cardiovascular health status.ObjectiveTo evaluate the association between midlife wealth mobility and risk of cardiovascular events.Design, setting, and participantsThis longitudinal, retrospective cohort study included US adults 50 years or older who participated in the Health and Retirement Study. Participants in the primary analysis had no history of cardiovascular disease and had observations in at least two of three 5-year age intervals (50-54, 55-59, and 60-64 years) and follow-up after 65 years of age. Data were collected from January 1, 1992, to December 31, 2016, and analyzed from November 10, 2020, to April 26, 2021.ExposuresQuintiles of wealth (reflecting total nonhousing assets) were defined within each of 4 birth cohorts (1931-1935, 1936-1940, 1941-1945, and 1946-1950). Wealth mobility was defined as an increase or a decrease of 1 or more wealth quintiles and was compared with wealth stability (same quintile over time) using covariate-adjusted Cox proportional hazards regression models.Main outcomes and measuresComposite outcome of nonfatal cardiovascular event (myocardial infarction, heart failure, cardiac arrhythmia, or stroke) or cardiovascular death.ResultsA total of 5579 participants were included in the primary analysis (mean [SD] age, 54.2 [2.6] years; 3078 women [55.2%]). During a mean (SD) follow-up of 16.9 (5.8) years, 1336 participants (24.0%) experienced a primary end point of nonfatal cardiovascular event or cardiovascular death (14.4 [95% CI, 13.6-15.2] per 1000 patient-years). Higher initial wealth (per quintile) was associated with lower cardiovascular risk (adjusted hazard ratio [aHR] per quintile, 0.89 [95% CI, 0.84-0.95]; P = .001). When compared with stable wealth, participants who experienced upward wealth mobility (by at least 1 quintile) had independently lower hazards of a subsequent nonfatal cardiovascular event or cardiovascular death (aHR, 0.84 [95% CI, 0.73-0.97]; P = .02), and participants who experienced downward wealth mobility had higher risks (aHR, 1.15 [95% CI, 1.00-1.32]; P = .046).Conclusions and relevanceThese findings suggest that upward wealth mobility relative to peers in late middle age is associated with lower risks of cardiovascular events or death after 65 years of age.

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

Publications

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

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