Faye Lopez

Placental Insufficiency Leads to Developmental Hypertension and Mesenteric Artery Dysfunction in Two Generations of Sprague-Dawley Rat Offspring

Abstract It is generally accepted that preeclampsia results from reduction in perfusion to the uteroplacental unit leading to maternal hypertension and fetal growth restriction. Placental insufficiency creates an environment of fetal undernutriton, predisposing the fetus to the development of adult disease. In this study, we characterized the development and perpetuation of hypertension in two generations of male and female offspring subjected to an environment of fetal undernutrition via reduced uteroplacental perfusion pressure. Further, we examined vascular responses of resistance arteries in these animals to determine the influence of placental insufficiency on the development and perpetuation of hypertension. Experimental dams underwent a surgical procedure to reduce uteroplacental perfusion pressure, with resulting offspring comprising the first generation (F1). One male and one female from each of the F1 experimental litters served as breeders of the second generation (F2). Weekly systolic blood pressure measurements were obtained from 4 to 24 wk in control, F1, and F2 offspring. Vascular responsiveness to the vasoconstrictors phenylephrine and potassium chloride and the vasorelaxants acetylcholine and sodium nitroprusside was determined in the three offspring groups at 6, 9, and 12 wk of age. Our findings indicate that placental insufficiency during a critical developmental window in late gestation leads to hypertension in juvenile Sprague-Dawley rat offspring and is perpetuated in a second generation of offspring in a gender-specific manner. Further, exposure to placental insufficiency during late gestation leads to developmental alterations characterized by vascular hyperresponsiveness, perpetuated to a second generation of offspring in the absence of persistent environmental stimuli, contributing to hypertension.

Reduced uteroplacental perfusion alters uterine arcuate artery function in the pregnant Sprague-Dawley rat

Abstract Evidence continues to implicate reduced placental perfusion as the cause of preeclampsia, initiating a sequence of events leading to altered vascular function and hypertension. The present study was designed to determine the influence of reduced uteroplacental perfusion pressure (RUPP) on the responsiveness of uterine arcuate resistance arteries. A condition of RUPP was surgically induced in pregnant Sprague-Dawley rats on Gestational Day 14. On Gestational Day 20, uterine arcuate arteries were mounted on a small-vessel wire myograph and challenged with incremental concentrations of vasoconstrictors and vasorelaxants for measurement of isometric tension. Compared to the sham-operated controls, uterine arteries from the RUPP group demonstrated an increased maximal tension in response to phenylephrine (P < 0.01); potassium chloride at 30 mM (P < 0.05), 60 mM (P < 0.01), and 120 mM (P < 0.01); and angiotensin II (P < 0.05). In arteries from the RUPP and sham-operated control groups, endothelium-dependent relaxation in response to acetylcholine (P < 0.05) and calcium ionophore (A23187; P < 0.05) was significantly reduced in the RUPP group compared to the sham-operated controls. Fetal growth indices, including litter size, fetal weight, and placental weight, were significantly reduced in the RUPP group compared to sham-operated controls, which is consistent with significant growth restriction. Data suggest that RUPP promotes hyperresponsiveness and impaired endothelium-dependent relaxation in uterine arcuate arteries, leading to intrauterine fetal growth restriction.

CARDIAC OVEREXPRESSION OF INSULIN-LIKE GROWTH FACTOR 1 ATTENUATES CHRONIC ALCOHOL INTAKE-INDUCED MYOCARDIAL CONTRACTILE DYSFUNCTION BUT NOT HYPERTROPHY: ROLES OF AKT, MTOR, GSK3BETA, AND PTEN

Chronic alcohol intake leads to the development of alcoholic cardiomyopathy manifested by cardiac hypertrophy and contractile dysfunction. This study was designed to examine the effects of transgenic overexpression of insulin-like growth factor 1 (IGF-1) on alcohol-induced cardiac contractile dysfunction. Wild-type FVB and cardiac-specific IGF-1 mice were placed on a 4% alcohol or control diet for 16weeks. Cardiac geometry and mechanical function were evaluated by echocardiography and cardiomyocyte and intracellular Ca(2+) properties. Histological analyses for cardiac fibrosis and apoptosis were evaluated by Masson trichrome staining and TUNEL assay, respectively. Expression and phosphorylation of Cu/Zn superoxide dismutase (SOD1), Ca(2+) handling proteins, and key signaling molecules for survival including Akt, mTOR, GSK3beta, Foxo3a, and the negative regulator of Akt, phosphatase and tensin homolog on chromosome 10 (PTEN), as well as mitochondrial proteins UCP-2 and PGC1alpha, were evaluated by Western blot analysis. Chronic alcohol intake led to cardiac hypertrophy, interstitial fibrosis, reduced mitochondrial number, compromised cardiac contractile function and intracellular Ca(2+) handling, decreased SOD1 expression, elevated superoxide production, and overt apoptosis, all of which, with the exception of cardiac hypertrophy, were abrogated by the IGF-1 transgene. Immunoblotting data showed reduced phosphorylation of Akt, mTOR, GSK3beta, and Foxo3a; upregulated Foxo3a and PTEN; and dampened SERCA2a, PGC1alpha, and UCP-2 after alcohol intake. All these alcohol-induced changes in survival and mitochondrial proteins were alleviated by IGF-1. Taken together, these data favor a beneficial role for IGF-1 in alcohol-induced myocardial contractile dysfunction independent of cardiac hypertrophy.

Mesenteric vascular responsiveness in a rat model of pregnancy-induced hypertension.

Reduced perfusion to the placenta in early pregnancy is believed to be the initiating factor in the development of preeclampsia, triggering local ischemia and systemic vascular hyperresponsiveness. This sequence of events creates a predisposition to the development of altered vascular function and hypertension. This study was designed to determine the influence of placental insufficiency on the responsiveness of mesenteric resistance arteries in an animal model of preeclampsia. Placental insufficiency was induced by reduction in uteroplacental perfusion pressure (RUPP) in experimental Sprague-Dawley rat dams. The uterine branches of the ovarian arteries and the abdominal aortae of pregnant rats were surgically constricted on gestational Day 14. Dams in the control group underwent a sham procedure. Rats were euthanized on gestational Day 20, followed by removal of the small intestine and adjacent mesentery. First-order mesenteric resistance arteries were mounted on a small vessel wire myograph and challenged with incremental concentrations of vasoconstrictors and vasorelaxants. Mesenteric arteries in dams with placental insufficiency demonstrated an increased maximal tension to phenylephrine (7.15 ± 0.15 vs. 5.4 ± 0.27 mN/mm, P < 0.001); potassium chloride at 60 mM (3.43 ± 0.11 vs. 2.77 ± 0.14 mN/mm, P < 0.01) and 120 mM (3.92 ± 0.18 vs. 2.97 ± 0.16 mN/mm, P < 0.01); and angiotensin II (2.59 ± 0.42 vs. 1.51 ± 0.22 mN/mm, P < 0.05). Maximal relaxation to endothelium-dependent relaxants acetylcholine and calcium lonophore (A23187) was not significantly reduced. Data suggest that placental insufficiency leads to hyperresponsiveness to vasoconstrictor stimuli in mesenteric arteries.

Comparison of cardiac contractile and intracellular Ca2+ response between estrogen and phytoestrogen α-zearalanol in ventricular myocytes

While the benefit and risk of estrogen replacement therapy for cardiovascular disease remains controversial, women frequently choose alternatives to estrogen such as phytoestrogen for treatment of menopause even though medical indications for estrogens may exist. Phytoestrogens also possess distinct advantages over mammalian estrogens because their usage in men without feminizing side effects. Nevertheless, the cardiac contractile function of estrogen or phytoestrogen has not been clearly elucidated. The aim of the present study was to compare the effect of 17β estradiol (E2) and phytoestrogen α-zearalanol (ZAL) on cardiac mechanical function and intracellular Ca2+ transients at cellular levels. Isolated ventricular myocytes from adult female rats were stimulated to contract at 0.5 Hz. Contractile properties were evaluated using an IonOptix MyoCam® system including peak shortening (PS), time-to-PS (TPS), time-to-90% relengthening (TR90), and maximal velocity of shortening/relengthening (± dL/dt). Intracellular Ca2+ properties were evaluated as fura-2 fluorescent intensity change (ΔFFI) and intracellular Ca2+ decay rate. Acute administration of E2 (10−9–10−5M) elicited a concentration-dependent increase in PS and ΔFFI, with maximal augmentation of approx 35% and 25%, respectively. TPS, TR90, ± dL/dt, resting intracellular Ca2+ level, and intracellular Ca2+ decay were unaffected by E2. None of the mechanical or intracellular Ca2+ indices tested was affected by phytoestrogen ZAL (10−9–10−5M). Our results revealed a direct cardiac stimulatory action from E2 but not from phytoestrogen ZAL on ventricular contraction, likely mediated through enhanced intracellular Ca2+ release.

Placental insufficiency: programming of leptin secretion, blood pressure, and postnatal growth in two generations of Sprague-Dawley rats.

Regulatory process may be altered in response to the intrauterine environment, leading to the development of altered growth trajectory and disease later in life. Previously, our lab reported reduced leptin levels in pregnant hypertensive Sprague-Dawley rat dams with placental insufficiency. The purposes of this study were to investigate the relationship between leptin levels, growth and hypertension in two generations of offspring exposed to placental insufficiency. Leptin levels were significantly different only at 12 weeks in female first generation offspring (p < 0.05). Variations in postnatal body and organ weights were evident in first generation females at 3 and 12 weeks of age. There were no significant correlations with plasma leptin levels and systolic blood pressure in offspring groups at any age point. Our findings indicate that fetal exposure to maternal hypertension and hypoleptinemia is associated with altered leptin and growth patterns in mature female offspring and not perpetuated to a second generation.