Sustained Elevated Circulating Activin A Impairs Global Longitudinal Strain in Pregnant Rats: A Potential Mechanism for Preeclampsia-Related Cardiac Dysfunction

Mediators of cardiac injury in preeclampsia are not well understood. Preeclamptic women have decreased cardiac global longitudinal strain (GLS), a sensitive measure of systolic function that indicates fibrosis and tissue injury. GLS is worse in preeclampsia compared to gestational hypertension, despite comparable blood pressure, suggesting that placental factors may be involved. We previously showed that Activin A, a pro-fibrotic factor produced in excess by the placenta in preeclampsia, predicts impaired GLS postpartum. Here, we hypothesized that chronic excess levels of Activin A during pregnancy induces cardiac dysfunction. Rats were assigned to sham or activin A infusion (1.25–6 µg/day) on a gestational day (GD) 14 (n = 6–10/group). All animals underwent blood pressure measurement and comprehensive echocardiography followed by euthanasia and the collection of tissue samples on GD 19. Increased circulating activin A (sham: 0.59 ± 0.05 ng/mL, 6 µg/day: 2.8 ± 0.41 ng/mL, p p < 0.01). Activin A infusion (6 µg/day) increased beta-myosin heavy chain expression in heart tissue, indicating cardiac injury. In summary, our findings indicate that increasing levels of activin A during pregnancy induces cardiac dysfunction and supports the concept that activin A may serve as a possible mediator of PE-induced cardiac dysfunction

Heme oxygenase-1 is a potent inhibitor of placental ischemia-mediated endothelin-1 production in cultured human glomerular endothelial cells

Preeclampsia is a pregnancy-specific disorder of maternal hypertension and reduced renal hemodynamics linked to reduced endothelial function. Placental ischemia is thought to be the culprit of this disease, as it causes the release of factors like tumor necrosis factor (TNF)-α that induce vascular endothelin-1 (ET-1) production. Interestingly, placental ischemia-induced hypertension in rats [reduced uterine perfusion pressure (RUPP) model] is abolished by ETA receptor blockade, suggesting a critical role for ET-1. Although it has been found that systemic induction of heme oxygenase (HO)-1 is associated with reduced ET-1 production and attenuated hypertension, it is unclear whether HO-1 directly modulates the increased ET-1 response to placental factors. We tested the hypothesis that HO-1 or its metabolites inhibit ET-1 production in human glomerular endothelial cells induced by serum of RUPP rats or TNF-α. Serum (5%) from RUPP hypertensive (mean arterial blood pressure 119 ± 9 mmHg) vs. normotensive pregnant (NP, 101 ± 6 mmHg, P &lt; 0.001) rats increased ET-1 production (RUPP 168.8 ± 18.1 pg/ml, NP 80.3 ± 22.7 pg/ml, P &lt; 0.001, n = 12/group). HO-1 induction [25 µM cobalt photoporphyrin (CoPP)] abolished RUPP serum-induced ET-1 production (1.6 ± 0.8 pg/ml, P &lt; 0.001), whereas bilirubin (10 µM) significantly attenuated ET-1 release (125.3 ± 5.2 pg/ml, P = 0.005). Furthermore, TNF-α-induced ET-1 production (TNF-α 31.0 ± 8.4 vs. untreated 7.5 ± 0.4 pg/ml, P &lt; 0.001) was reduced by CoPP (1.5 ± 0.8 pg/ml, P &lt; 0.001) and bilirubin (10.5 ± 4.3 pg/ml, P &lt; 0.001). These results suggest that circulating factors released during placental ischemia target the maternal glomerular endothelium to increase ET-1, and that pharmacological induction of HO-1 or bilirubin could be a treatment strategy to block this prohypertensive pathway in preeclampsia. </jats:p

Prenatal Sildenafil Therapy Improves Cardiovascular Function in Fetal Growth Restricted Offspring of Dahl Salt-Sensitive Rats

Fetal growth restriction (FGR) is associated with increased risk for cardiovascular and renal disorders in later life. Prenatal sildenafil improves birth weight in FGR animal models. Whether sildenafil treatment protects against long-term cardiovascular and renal disease in these offspring is unknown. The aim of this study is to test the hypothesis that prenatal sildenafil ameliorates cardiovascular and renal function in FGR offspring of Dahl salt-sensitive rats. Sildenafil citrate (60 mg/kg per day) or control gel diet (containing 0.3% salt) was administered from gestational day ten until birth. In male and female offspring, the mean arterial pressure was measured by telemetry in 1 subset from week 5 until week twenty. Echocardiographic parameters, glomerular filtration rate, and fractional electrolyte excretion were determined in another subset at week 9. Aortic and mesenteric artery rings were prepared to assess endothelial-dependent (acetylcholine) and -independent (sodium nitroprusside) vasorelaxation (week 10). The rise in mean arterial pressure per week was attenuated in treated versus untreated male offspring. Mesenteric arteries showed an increased endothelium-dependent relaxation and improved endothelium-independent relaxation in treated versus control male offspring. No differences in aortic relaxation, echocardiographic parameters or renal function were observed between groups. Prenatal sildenafil treatment subtly improves cardiovascular but not renal function in the offspring of this FGR rat model. Translationally, in utero treatment could be beneficial for cardiovascular programming in a sex-specific manner; however, caution is warranted since recent human trials have been halted because of potentially deleterious neonatal side effects when treating pregnancies complicated with severe FGR with sildenafil

Exposure to placental ischemia impairs postpartum maternal renal and cardiac function in rats

INTRODUCTION: Women with a history of preeclampsia (PE) have an increased risk to develop cardiovascular and renal diseases later in life, but the mechanisms underlying this effect are unknown. In rats, we assessed whether placental ischemia results in long-term effects on the maternal cardiovascular and renal systems using the Reduced Uterine Perfusion Pressure (RUPP) model for PE. METHODS: Sprague-Dawley rats received either a SHAM or RUPP operation at gestational day 14. The rats were followed for eight weeks after delivery (SHAM n=12, RUPP n=21) at which time mean arterial pressure (MAP; conscious), 24-hour albuminuria, GFR (transcutaneous, FITC-sinistrin), and cardiac function (Vevo 770 system) were assessed. Subsequently, all rats were sacrificed for mesenteric artery vasorelaxation and histology of heart and kidney. RESULTS: At eight weeks after delivery, there was no difference in MAP and albuminuria. However, RUPP rats showed a significantly reduced GFR [2.61 ± 0.53 vs 3.37 ± 0.74ml/min; p=0.01]. Ultrasound showed comparable cardiac structure, but RUPP rats had a lower left ventricular ejection fraction (62 ± 7 vs 69 ± 10%; p=0.04). Heart and kidney histology was not different between SHAM or RUPP rats. Furthermore, there were no differences in endothelial dependent or independent vasorelaxation. CONCLUSIONS: We show that exposure to placental ischemia in rats is accompanied by functional disturbances in maternal renal and cardiac function eight weeks after a preeclamptic pregnancy. However, these changes were not dependent on differences in blood pressure, small artery vasorelaxation, or cardiac and renal structure at this time point postpartum

Exposure to placental ischemia impairs postpartum maternal renal and cardiac function in rats

INTRODUCTION: Women with a history of preeclampsia (PE) have an increased risk to develop cardiovascular and renal diseases later in life, but the mechanisms underlying this effect are unknown. In rats, we assessed whether placental ischemia results in long-term effects on the maternal cardiovascular and renal systems using the Reduced Uterine Perfusion Pressure (RUPP) model for PE. METHODS: Sprague-Dawley rats received either a SHAM or RUPP operation at gestational day 14. The rats were followed for eight weeks after delivery (SHAM n=12, RUPP n=21) at which time mean arterial pressure (MAP; conscious), 24-hour albuminuria, GFR (transcutaneous, FITC-sinistrin), and cardiac function (Vevo 770 system) were assessed. Subsequently, all rats were sacrificed for mesenteric artery vasorelaxation and histology of heart and kidney. RESULTS: At eight weeks after delivery, there was no difference in MAP and albuminuria. However, RUPP rats showed a significantly reduced GFR [2.61 ± 0.53 vs 3.37 ± 0.74ml/min; p=0.01]. Ultrasound showed comparable cardiac structure, but RUPP rats had a lower left ventricular ejection fraction (62 ± 7 vs 69 ± 10%; p=0.04). Heart and kidney histology was not different between SHAM or RUPP rats. Furthermore, there were no differences in endothelial dependent or independent vasorelaxation. CONCLUSIONS: We show that exposure to placental ischemia in rats is accompanied by functional disturbances in maternal renal and cardiac function eight weeks after a preeclamptic pregnancy. However, these changes were not dependent on differences in blood pressure, small artery vasorelaxation, or cardiac and renal structure at this time point postpartum

Bilirubin acts as a multi-potent guardian of cardiovascular integrity: more than just a radical idea

Bilirubin, a potentially toxic catabolite of heme and indicator of hepato-biliary insufficiency, exhibits potent cardiac and vascular protective properties. Individuals with Gilbert's syndrome (GS) may experience hyperbilirubinemia in response to stressors including reduced hepatic bilirubin excretion/increased red blood cell breakdown, with individuals usually informed by their clinician that their condition is of little consequence. However, GS appears to protect from all-cause mortality, with progressively elevated total bilirubin associated with protection from ischemic heart and chronic obstructive pulmonary diseases. Bilirubin may protect against these diseases and associated mortality by reducing circulating cholesterol, oxidative lipid/protein modifications and blood pressure. In addition, bilirubin inhibits platelet activation and protects the heart from ischemia-reperfusion (I-R) injury. These effects attenuate multiple stages of the atherosclerotic process, in addition to protecting the heart during resultant ischemic stress, likely underpinning the profound reduction in cardiovascular mortality in hyperbilirubinemic GS. This review outlines our current knowledge of and uses for bilirubin in clinical medicine, and summarises recent progress in revealing the physiological importance of this poorly understood molecule. We believe that this review will be of significant interest to clinicians, medical researchers and individuals who have GS