Developmental origins of cardiovascular disease: Impact of early life stress in humans and rodents.

The Developmental Origins of Health and Disease (DOHaD) hypothesizes that environmental insults during childhood programs the individual to develop chronic disease in adulthood. Emerging epidemiological data strongly supports that early life stress (ELS) given by the exposure to adverse childhood experiences is regarded as an independent risk factor capable of predicting future risk of cardiovascular disease. Experimental animal models utilizing chronic behavioral stress during postnatal life, specifically maternal separation (MatSep) provides a suitable tool to elucidate molecular mechanisms by which ELS increases the risk to develop cardiovascular disease, including hypertension. The purpose of this review is to highlight current epidemiological studies linking ELS to the development of cardiovascular disease and to discuss the potential molecular mechanisms identified from animal studies. Overall, this review reveals the need for future investigations to further clarify the molecular mechanisms of ELS in order to develop more personalized therapeutics to mitigate the long-term consequences of chronic behavioral stress including cardiovascular and heart disease in adulthood.

A mechanistic look at the effects of adversity early in life on cardiovascular disease risk during adulthood.

Early origins of adult disease may be defined as adversity or challenges during early life that alter physiological responses and prime the organism to chronic disease in adult life. Adverse childhood experiences or early life stress (ELS) may be considered a silent independent risk factor capable of predicting future cardiovascular disease risk. Maternal separation (MatSep) provides a suitable model to elucidate the underlying molecular mechanisms by which ELS increases the risk to develop cardiovascular disease in adulthood. The aim of this review is to describe the links between behavioural stress early in life and chronic cardiovascular disease risk in adulthood. We will discuss the following: (i) adult cardiovascular outcomes in humans subjected to ELS, (ii) MatSep as an animal model of ELS as well as the limitations and advantages of this model in rodents and (iii) possible ELS-induced mechanisms that predispose individuals to greater cardiovascular risk. Overall, exposure to a behavioural stressor early in life sensitizes the response to a second stressor later in life, thus unmasking an exaggerated cardiovascular dysfunction that may influence quality of life and life expectancy in adulthood.

Importancia de la ciclooxigenasa-2 en la regulación de la hemodinámica renal durante la gestación en ratas conscientes / Role of COX-2 in regulating renal hemodynamics during gestation in conscious rats

Objetivo. Determinar la importancia de la ciclooxigenasa-2 (COX-2) en la regulación de la hemodinámica renal durante la gestación en ratas. Material y método. En primer lugar se determinó la expresión renal de la COX-2 a lo largo de la gestación mediante la técnica de western blot. La expresión de la COX-2 fue analizada en los siguientes grupos de ratas: ratas vírgenes (n = 6), ratas en los días 6 (n = 6), 13 (n = 6) y 20 de gestación (n = 6) y ratas en el día 4 después del parto (n = 6). El análisis densitométrico de los diferentes western blot demostró que los niveles de la proteína aumentaron (p < 0,05) un 41 % en la segunda semana de gestación con respecto a los observados en ratas vírgenes. En segundo lugar se determinó el efecto de la inhibición específica de la COX-2 sobre los cambios en la hemodinámica renal observados durante la mitad de la gestación. Los experimentos se realizaron en ratas vírgenes (n = 10) y ratas gestantes (n = 10) tratadas con vehículo (salino isotónico) o con el inhibidor específico de la COX-2 (rofecoxib). El inhibidor de la COX-2 fue administrado por vía oral durante tres días (10 mg/kg/día). Las medidas de presión arterial media (PAM), flujo plasmático renal (FPR) y tasa de filtración glomerular (TFG) fueron realizadas en el día 14 de gestación. Resultados. De acuerdo con estudios previos, la resistencia vascular renal (RVR) fue menor (p < 0,05) en el grupo de ratas gestantes (35 ± 3 mmHg/ml · min­1 · g­1) que en el grupo de ratas vírgenes tratadas con vehículo (46 ± 5 mmHg/ml · min­1 · g­1). Del mismo modo, la TFG fue mayor (p < 0,05) en las ratas gestantes (1,43 ± 0,16 ml/min/g) que en las ratas vírgenes tratadas con vehículo (0,99 ± 0,06 ml/min/g). La administración oral de rofecoxib no alteró la TFG ni la PAM en ninguno de los dos grupos de animales. Por el contrario, el tratamiento con el inhibidor específico de la COX-2 provocó una disminución significativa (p < 0,05) en la RVR en el grupo de ratas preñadas (27 ± 2 mmHg/ml · min­1 · g ­1), sin afectar la RVR en el grupo de ratas vírgenes (49 ± 4 mmHg/ ml · min­1 · g­1). Conclusión. Los resultados de este estudio sugieren que la COX-2 está implicada en la regulación de la hemodinámica renal durante la gestación en ratas conscientes

Objective. The purpose of this study was to determine the role of cyclooxygenase-2 (COX-2) in regulating renal hemodynamics during mid-gestation in the rat. Material and methods. Renal COX expression was determined by western blot analysis in kidneys from virgin rats (n = 6), pregnant rats at days 6 (n = 6), 13 (n = 6) and 20 (n = 6) of pregnancy and rats at day 4 postpartum (n = 6). Protein levels at day 13 of gestation were 41 % higher than in virgin rats. To evaluate whether the increase in COX-2 expression was involved in regulating renal hemodynamics during midpregnancy in the rat, we also tested the effects of a specific inhibitor of COX-2 (rofecoxib) on renal vascular resistance (RVR) and glomerular filtration rate (GFR) in virgin and mid-pregnant rats. Studies were conducted in four experimental groups: virgin rats + vehicle (n = 10), virgin rats + rofecoxib (n = 10), pregnant rats + vehicle (n = 10) and pregnant rats + rofecoxib (n = 10). Rofecoxib was administered by gavage over 3 days, at a dose of 10 mg/kg/day. Mean arterial pressure (MAP), renal plasma flow (RPF) and GFR were determined at day 14 of gestation. Results. Consistent with earlier reports, midterm pregnant rats showed a significantly (p < 0.05) lower RVR (35 ± 3 mmHg/ml · min­1 · g­1) than virgin controls (46 ± 5 mmHg/ ml · min­1 · g­1). Baseline GFR for gravid rats was significantly (p < 0.05) higher (1.43 ± 0.16 ml/min/g) than in virgin rats (0.99 ± 0.06 ml · min­1 · g­1). COX-2 inhibition with rofecoxib reduced RVR in pregnant rats (27 ± 2 mmHg/ml · min­1 · g­1), whereas it had not effect on RVR in virgin controls (49 ± 4 mmHg/ml · min­1 · g ­1). Conclusion. These data suggest that COX-2 is involved in regulating renal hemodynamics during gestation in conscious rats