RESUMO
A significant number of pregnancies occur at advanced maternal age (>35 yr), which is a risk factor for pregnancy complications. Healthy pregnancies require massive hemodynamic adaptations, including an increased blood volume and cardiac output. There is growing evidence that these cardiovascular adaptations are impaired with age, however, little is known about maternal cardiac function with advanced age. We hypothesized that cardiac adaptations to pregnancy are impaired with advanced maternal age. Younger (4 mo; â¼early reproductive maturity in humans) and aged (9 mo; â¼35 yr in humans) pregnant Sprague-Dawley rats were assessed and compared with age-matched nonpregnant controls. Two-dimensional echocardiographic images were obtained (ultrasound biomicroscopy; under anesthesia) on gestational day 19 (term = 22 days) and compared with age-matched nonpregnant rats (n = 7-9/group). Left ventricular structure and function were assessed using short-axis images and transmitral Doppler signals. During systole, left ventricular anterior wall thickness increased with age in the nonpregnant rats, but there was no age-related difference between the pregnant groups. There were no significant pregnancy-associated differences in left ventricular wall thickness. Calculated left ventricular mass increased with age in nonpregnant rats and increased with pregnancy only in young rats. Compared with young pregnant rats, the aortic ejection time of aged pregnant rats was greater and Tei index was lower. Overall, the greater aortic ejection time and lower Tei index with age in pregnant rats suggest mildly altered cardiac adaptations to pregnancy with advanced maternal age, which may contribute to adverse outcomes in advanced maternal age pregnancies.NEW & NOTEWORTHY We demonstrated that even before the age of reproductive senescence, rats show signs of age-related alterations in cardiac structure that suggests increased cardiac work. Our data also demonstrate, using an in vivo echocardiographic approach, that advanced maternal age in a rat model is associated with altered cardiac function and structure relative to younger pregnant controls.
Assuntos
Ecocardiografia , Coração , Gravidez , Feminino , Humanos , Ratos , Animais , Idade Materna , Ratos Sprague-Dawley , Coração/diagnóstico por imagem , Débito CardíacoRESUMO
Hypercholesterolemia in pregnancy is a physiological process required for normal fetal development. In contrast, excessive pregnancy-specific hypercholesterolemia increases the risk of complications, such as preeclampsia. However, the underlying mechanisms are unclear. Toll-like receptor 4 (TLR4) is a membrane receptor modulated by high cholesterol levels, leading to endothelial dysfunction; but whether excessive hypercholesterolemia in pregnancy activates TLR4 is not known. We hypothesized that a high cholesterol diet (HCD) during pregnancy increases TLR4 activity in uterine arteries, leading to uterine artery dysfunction. Sprague Dawley rats were fed a control diet (n=12) or HCD (n=12) during pregnancy (gestational day 6-20). Vascular function was assessed in main uterine arteries using wire myography (vasodilation to methacholine and vasoconstriction to phenylephrine; with and without inhibitors for mechanistic pathways) and pressure myography (biomechanical properties). Exposure to a HCD during pregnancy increased maternal blood pressure, induced proteinuria, and reduced the fetal-to-placental weight ratio for both sexes. Excessive hypercholesterolemia in pregnancy also impaired vasodilation to methacholine in uterine arteries, whereby at higher doses, methacholine caused vasoconstriction instead of vasodilation in only the HCD group, which was prevented by inhibition of TLR4 or prostaglandin H synthase 1. Endothelial nitric oxide synthase expression and nitric oxide levels were reduced in HCD compared with control dams. Vasoconstriction to phenylephrine and biomechanical properties were similar between groups. In summary, excessive hypercholesterolemia in pregnancy impairs uterine artery function, with TLR4 activation as a key mechanism. Thus, TLR4 may be a target for therapy development to prevent adverse perinatal outcomes in complicated pregnancies.
Assuntos
Hipercolesterolemia , Hiperlipidemias , Animais , Feminino , Masculino , Gravidez , Ratos , Hipercolesterolemia/metabolismo , Hiperlipidemias/metabolismo , Cloreto de Metacolina/metabolismo , Fenilefrina/farmacologia , Fenilefrina/metabolismo , Placenta , Ratos Sprague-Dawley , Receptor 4 Toll-Like/metabolismo , Artéria Uterina/metabolismo , Vasodilatação/fisiologiaRESUMO
BACKGROUND: Gestational dyslipidemia is associated with pregnancy complications including preeclampsia. However, whether gestational dyslipidemia leads postpartum vascular dysfunction, which could increase the risk for cardiovascular complications later in life, is not known. Here, we aimed to determine whether a gestational dyslipidemia affects postpartum vascular health and induces early signs of atherosclerosis. METHODS: Pregnant C57BL/6 mice received a high cholesterol diet or control diet from gestational day 13.5 until term. After delivery, all mice received the control diet for ≈3 months postpartum (PP). Age-matched nulliparous females were on the same diets for equal periods. After 3 months, all mice were euthanized, serum was collected, and aortas were isolated to assess vascular function (wire myography) and markers of oxidative stress and early atherosclerosis. RESULTS: PP-high cholesterol diet females had increased circulating cholesterol levels compared with PP-control diet mice, without effect of the diet in nulliparous mice. Methacholine-induced vasodilation was impaired, and nitric oxide contribution reduced, by the high cholesterol diet in aortas of PP mice, but not in nulliparous mice. Exposure to oxidized low-density-protein cholesterol further impaired methylcholine-induced vasodilation in PP-high cholesterol diet aortas only. Compared with PP-control diet mice, aortic inducible nitric oxide synthase expression, reactive oxygen species and nitrotyrosine levels were increased in aortas from PP-high cholesterol diet mice. No differences in aortic lipid deposition and macrophage infiltration were found. CONCLUSIONS: Exposure to a high cholesterol diet in pregnancy impairs vascular function postpartum. Our results support the hypothesis that gestational dyslipidemia impacts maternal vascular function after pregnancy, which could potentially predispose these women to future cardiovascular complications.
Assuntos
Aterosclerose , Hipercolesterolemia , Humanos , Gravidez , Camundongos , Feminino , Animais , Camundongos Endogâmicos C57BL , Vasodilatação , Dieta , Colesterol/farmacologiaRESUMO
Prenatal hypoxia is associated with enhanced susceptibility to cardiac ischemia-reperfusion (I/R) injury in adult offspring, however, the mechanisms remain to be fully investigated. Endothelin-1 (ET-1) is a vasoconstrictor that acts via endothelin A (ETA) and endothelin B (ETB) receptors and is essential in maintaining cardiovascular (CV) function. Prenatal hypoxia alters the ET-1 system in adult offspring possibly contributing to I/R susceptibility. We previously showed that ex vivo application of ETA antagonist ABT-627 during I/R prevented the recovery of cardiac function in prenatal hypoxia-exposed males but not in normoxic males nor normoxic or prenatal hypoxia-exposed females. In this follow-up study, we examined whether placenta-targeted treatment with a nanoparticle-encapsulated mitochondrial antioxidant (nMitoQ) during hypoxic pregnancies could alleviate this hypoxic phenotype observed in adult male offspring. We used a rat model of prenatal hypoxia where pregnant Sprague-Dawley rats were exposed to hypoxia (11% O2) from gestational days (GD) 15-21 after injection with 100 µL saline or nMitoQ (125 µM) on GD15. Male offspring were aged to 4 mo and ex vivo cardiac recovery from I/R was assessed. Offspring born from hypoxic pregnancies and treated with nMitoQ had increased cardiac recovery from I/R in the presence of ABT-627 compared with their untreated counterparts where ABT-627 prevented recovery. Cardiac ETA levels were increased in males born from hypoxic pregnancies with nMitoQ treatment compared with saline controls (Western blotting). Our data indicate a profound impact of placenta-targeted treatment to prevent an ETA receptor cardiac phenotype observed in adult male offspring exposed to hypoxia in utero.NEW & NOTEWORTHY In this follow-up study, we showed a complete lack of recovery from I/R injury after the application of an ETA receptor antagonist (ABT-627) in adult male offspring exposed to hypoxia in utero while maternal treatment with nMitoQ during prenatal hypoxia exposure prevented this effect. Our data suggest that nMitoQ treatment during hypoxic pregnancies may prevent a hypoxic cardiac phenotype in adult male offspring.
Assuntos
Hipóxia , Receptores de Endotelina , Gravidez , Feminino , Ratos , Masculino , Animais , Ratos Sprague-Dawley , Atrasentana , Seguimentos , Hipóxia/complicações , Placenta , Endotelina-1RESUMO
Prenatal hypoxia is associated with placental oxidative stress, leading to impaired fetal growth and an increased risk of cardiovascular disease in the adult offspring; however, the mechanisms are unknown. Alterations in mitochondrial function may result in impaired cardiac function in offspring. In this study, we hypothesized that cardiac mitochondrial function is impaired in adult offspring exposed to intrauterine hypoxia, which can be prevented by placental treatment with a nanoparticle-encapsulated mitochondrial antioxidant (nMitoQ). Cardiac mitochondrial respiration was assessed in 4-month-old rat offspring exposed to prenatal hypoxia (11% O2) from gestational day (GD)15-21 receiving either saline or nMitoQ on GD 15. Prenatal hypoxia did not alter cardiac mitochondrial oxidative phosphorylation capacity in the male offspring. In females, the NADH + succinate pathway capacity decreased by prenatal hypoxia and tended to be increased by nMitoQ. Prenatal hypoxia also decreased the succinate pathway capacity in females. nMitoQ treatment increased respiratory coupling efficiency in prenatal hypoxia-exposed female offspring. In conclusion, prenatal hypoxia impaired cardiac mitochondrial function in adult female offspring only, which was improved with prenatal nMitoQ treatment. Therefore, treatment strategies targeting placental oxidative stress in prenatal hypoxia may reduce the risk of cardiovascular disease in adult offspring by improving cardiac mitochondrial function in a sex-specific manner.
Assuntos
Antioxidantes , Doenças Cardiovasculares , Feminino , Masculino , Gravidez , Animais , Ratos , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Placenta , Vitaminas , Hipóxia/complicações , Hipóxia/tratamento farmacológico , Mitocôndrias , SuccinatosRESUMO
Fetal hypoxia, a major consequence of complicated pregnancies, impairs offspring cardiac tolerance to ischemia-reperfusion (I/R) insult; however, the mechanisms remain unknown. Endothelin-1 (ET-1) signaling through the endothelin A receptors (ETA) is associated with cardiac dysfunction. We hypothesized that prenatal hypoxia exacerbates cardiac susceptibility to I/R via increased ET-1 and ETA levels, whereas ETA inhibition ameliorates this. Pregnant Sprague-Dawley rats were exposed to normoxia (21% O2) or hypoxia (11% O2) on gestational days 15-21. Offspring were aged to 4 mo, and hearts were aerobically perfused or subjected to ex vivo I/R, with or without preinfusion with an ETA antagonist (ABT-627). ET-1 levels were assessed with ELISA in aerobically perfused and post-I/R left ventricles (LV). ETA and ETB levels were assessed by Western blotting in nonperfused LV. As hypothesized, ABT-627 infusion tended to improve post-I/R recovery in hypoxic females (P = 0.0528); however, surprisingly, ABT-627 prevented post-I/R recovery only in the hypoxic males (P < 0.001). ET-1 levels were increased in post-I/R LV in both sexes regardless of the prenatal exposure (P < 0.01). ETA expression was similar among all groups, whereas ETB (isoform C) levels were decreased in prenatally hypoxic females (P < 0.05). In prenatally hypoxic males, ETA signaling may be essential for tolerance to I/R, whereas in prenatally hypoxic females, ETA may contribute to cardiac dysfunction. Our data illustrate that understanding the prenatal history has critical implications for treatment strategies in adult chronic diseases.NEW & NOTEWORTHY We demonstrated that prenatal hypoxia (a common condition of pregnancy) can have profound differential effects on treatment strategies in adult cardiovascular disease. Our data using a rat model of prenatal hypoxia demonstrated that, as adults, although inhibition of endothelin (ETA) receptors before an ex vivo cardiac ischemic insult improved recovery in females, it strikingly prevented recovery in males. Our data indicate a sex-specific effect of prenatal hypoxia on the cardiac ET-1 system in adult offspring.
Assuntos
Cardiopatias , Hipóxia , Animais , Atrasentana , Endotelina-1 , Endotelinas , Feminino , Isquemia/complicações , Masculino , Gravidez , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina ARESUMO
Pregnancy complications associated with prenatal hypoxia lead to increased placental oxidative stress. Previous studies suggest that prenatal hypoxia can reduce mitochondrial respiratory capacity and mitochondrial fusion, which could lead to placental dysfunction and impaired fetal development. We developed a placenta-targeted treatment strategy using a mitochondrial antioxidant, MitoQ, encapsulated into nanoparticles (nMitoQ) to reduce placental oxidative stress and (indirectly) improve fetal outcomes. We hypothesized that, in a rat model of prenatal hypoxia, nMitoQ improves placental mitochondrial function and promotes mitochondrial fusion in both male and female placentae. Pregnant rats were treated with saline or nMitoQ on gestational day (GD) 15 and exposed to normoxia (21% O2 ) or hypoxia (11% O2 ) from GD15-21. On GD21, male and female placental labyrinth zones were collected for mitochondrial respirometry assessments, mitochondrial content, and markers of mitochondrial biogenesis, fusion and fission. Prenatal hypoxia reduced complex IV activity and fusion in male placentae, while nMitoQ improved complex IV activity in hypoxic male placentae. In female placentae, prenatal hypoxia decreased respiration through the S-pathway (complex II) and increased N-pathway (complex I) respiration, while nMitoQ increased fusion in hypoxic female placentae. No changes in mitochondrial content, biogenesis or fission were found. In conclusion, nMitoQ improved placental mitochondrial function in male and female placentae from fetuses exposed to prenatal hypoxia, which may contribute to improved placental function. However, the mechanisms (ie, changes in mitochondrial respiratory capacity and mitochondrial fusion) were distinct between the sexes. Treatment strategies targeted against placental oxidative stress could improve placental mitochondrial function in complicated pregnancies.
Assuntos
Antioxidantes/uso terapêutico , Hipóxia Fetal/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Nanopartículas/química , Compostos Organofosforados/uso terapêutico , Placenta/efeitos dos fármacos , Ubiquinona/análogos & derivados , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Respiração Celular , Feminino , Masculino , Mitocôndrias/metabolismo , Dinâmica Mitocondrial , Compostos Organofosforados/administração & dosagem , Compostos Organofosforados/farmacologia , Placenta/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley , Fatores Sexuais , Ubiquinona/administração & dosagem , Ubiquinona/farmacologia , Ubiquinona/uso terapêuticoRESUMO
Advanced maternal age (≥35 years) is associated with pregnancy complications. Aging impairs vascular reactivity and increases vascular stiffness. We hypothesized that uterine artery adaptations to pregnancy are impaired with advanced age. Uterine arteries of nonpregnant and pregnant (gestational day 20) young (4 months) and aged (9 months; ~35 years in humans) Sprague-Dawley rats were isolated. Functional (myogenic tone, n = 6−10/group) and mechanical (circumferential stress-strain, n = 10−24/group) properties were assessed using pressure myography and further assessment of elastin and collagen (histology, n = 4−6/group), and matrix metalloproteinase-2 (MMP-2, zymography, n = 6/group). Aged dams had worse pregnancy outcomes, including smaller litters and fetal weights (both p < 0.0001). Only in arteries of pregnant young dams did higher pressures (>100 mmHg) cause forced vasodilation. Across the whole pressure range (4−160 mmHg), myogenic behavior was enhanced in aged vs. young pregnant dams (p = 0.0010). Circumferential stress and strain increased with pregnancy in young and aged dams (p < 0.0001), but strain remained lower in aged vs. young dams (p < 0.05). Arteries from young nonpregnant rats had greater collagen:elastin ratios than the other groups (p < 0.05). In aged rats only, pregnancy increased MMP-2 active capacity. Altered functional and structural vascular adaptations to pregnancy may impair fetal growth and development with advanced maternal age.
Assuntos
Metaloproteinase 2 da Matriz , Artéria Uterina , Animais , Colágeno , Elastina , Feminino , Humanos , Idade Materna , Gravidez , Ratos , Ratos Sprague-DawleyRESUMO
Offspring born from complicated pregnancies are at greater risk of cardiovascular disease in adulthood. Prenatal hypoxia is a common pregnancy complication that results in placental oxidative stress and impairs fetal development. Adult offspring exposed to hypoxia during fetal life are more susceptible to develop cardiac dysfunction, and show decreased cardiac tolerance to an ischemia/reperfusion (I/R) insult. To improve offspring cardiac outcomes, we have assessed the use of a placenta-targeted intervention during hypoxic pregnancies, by encapsulating the mitochondrial antioxidant MitoQ into nanoparticles (nMitoQ). We hypothesized that maternal nMitoQ treatment during hypoxic pregnancies improves cardiac tolerance to I/R insult in adult male and female offspring. Pregnant Sprague-Dawley rats were exposed to normoxia (21 % O2) or hypoxia (11 % O2) from gestational day 15-20, after injection with 100 µL saline or nMitoQ (125 µM) on GD15 (n=6-8/group). Male and female offspring were aged to 4 months. Both male and female offspring from hypoxic pregnancies showed reduced cardiac tolerance to I/R (assessed ex vivo using the isolated working heart technique) which was ameliorated by nMitoQ treatment. To identify potential molecular mechanisms for the changes in cardiac tolerance to I/R, cardiac levels/phosphorylation of proteins important for intracellular Ca2+ cycling were assessed with Western blotting. In prenatally hypoxic male offspring, improved cardiac recovery from I/R by nMitoQ was accompanied by increased cardiac phospholamban and phosphatase 2Ce levels, and a trend to decreased Ca2+/calmodulin-dependent protein kinase IIδ phosphorylation. In contrast, in female offspring, nMitoQ treatment in hypoxic pregnancies increased phospholamban and protein kinase Cε phosphorylation. Maternal nMitoQ treatment improves cardiac tolerance to I/R insult in adult offspring and thus has the potential to improve the later-life trajectory of cardiovascular health of adult offspring born from pregnancies complicated by prenatal hypoxia.
Assuntos
Doenças Cardiovasculares/metabolismo , Hipóxia/metabolismo , Compostos Organofosforados/administração & dosagem , Placenta/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Traumatismo por Reperfusão/metabolismo , Ubiquinona/análogos & derivados , Fatores Etários , Animais , Antioxidantes/administração & dosagem , Doenças Cardiovasculares/prevenção & controle , Feminino , Hipóxia/tratamento farmacológico , Masculino , Nanopartículas/administração & dosagem , Placenta/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Ubiquinona/administração & dosagemRESUMO
The lectin-like oxidized low-density-lipoprotein (oxLDL) receptor-1 (LOX-1) has been shown to induce angiotensin II (AngII) type 1 receptor (AT1) activation, contributing to vascular dysfunction. Preeclampsia is a pregnancy complication characterized by vascular dysfunction and increased LOX-1 and AT1 activation; however, whether LOX-1 and AT1 activity contributes to vascular dysfunction in preeclampsia is unknown. We hypothesized that increased oxLDL levels during pregnancy lead to LOX-1 activation and subsequent AT1 activation, resulting in vascular dysfunction. Pregnant wild-type (WT) and transgenic LOX-1 overexpressing (LOX-1tg) mice were fed a control diet (CD) or high-cholesterol diet (HCD, to impair vascular function) between gestational day (GD) 13.5-GD18.5. On GD18.5, AngII-induced vasoconstriction and methylcholine (MCh)-induced endothelium-dependent vasodilation responses were assessed in aortas and uterine arteries. HCD decreased fetal weight and increased circulating oxLDL/cholesterol levels in WT, but not in LOX-1tg mice. HCD did not alter AngII responsiveness or AT1 expression in both vascular beds; however, AngII responsiveness and AT1 expression were lower in aortas from LOX-1tg compared with WT mice. In aortas from WT-CD mice, acute oxLDL exposure induced AT1-mediated vasoconstriction via LOX-1. HCD impaired endothelium-dependent vasodilation and increased superoxide levels in WT aortas, but not uterine arteries. Moreover, in WT-CD mice oxLDL decreased MCh sensitivity in both vascular beds, partially via LOX-1. In summary, HCD impaired pregnancy outcomes and vascular function, and oxLDL-induced LOX-1 activation may contribute to vascular dysfunction via AT1. Our study suggests that LOX-1 could be a potential target to prevent adverse outcomes associated with vascular dysfunction in preeclampsia.
Assuntos
Lipoproteínas LDL/farmacologia , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Depuradores Classe E/metabolismo , Doenças Vasculares/fisiopatologia , Angiotensina II , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Aorta/fisiopatologia , Peso Corporal/efeitos dos fármacos , Colesterol na Dieta , Colina/análogos & derivados , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Feminino , Feto/efeitos dos fármacos , Feto/patologia , Camundongos Transgênicos , Estresse Oxidativo/efeitos dos fármacos , Gravidez , Superóxidos/metabolismo , Artéria Uterina/patologia , Artéria Uterina/fisiopatologia , Doenças Vasculares/patologia , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
NEW FINDINGS: What is the central question of this study? Does treatment of hypoxic dams with a placenta-targeted antioxidant prevent the release of placenta-derived factors that impair maturation or growth of fetal cardiomyocytes in vitro? What is the main finding and its importance? Factors released from hypoxic placentae impaired fetal cardiomyocyte maturation (induced terminal differentiation) and growth (increased cell size) in vitro, which was prevented by maternal treatment with a placenta-targeted antioxidant (nMitoQ). Moreover, there were no sex differences in the effects of placental factors on fetal cardiomyocyte maturation and growth. Overall, our data suggest that treatment targeted against placental oxidative stress could prevent fetal programming of cardiac diseases via the release of placental factors. ABSTRACT: Pregnancy complications associated with placental oxidative stress may impair fetal organ development through the release of placenta-derived factors into the fetal circulation. We assessed the effect of factors secreted from placentae previously exposed to prenatal hypoxia on fetal cardiomyocyte development and developed a treatment strategy that targets placental oxidative stress by encapsulating the antioxidant MitoQ into nanoparticles (nMitoQ). We used a rat model of prenatal hypoxia (gestational day (GD) 15-21), which was treated with saline or nMitoQ on GD15. On GD21, placentae were harvested, placed in culture, and conditioned medium (containing placenta-derived factors) was collected after 24 h. This conditioned medium was then added to cultured cardiomyocytes from control dam fetuses. Conditioned medium from prenatally hypoxic placentae increased the percentage of binucleated cardiomyocytes (marker of terminal differentiation) and the size of mononucleated and binucleated cardiomyocytes (sign of hypertrophy), effects that were prevented by nMitoQ treatment. Our data suggest that factors derived from placentae previously exposed to prenatal hypoxia lead to abnormal fetal cardiomyocyte development, and show that treatment against placental oxidative stress may prevent fetal programming of cardiac disease.
Assuntos
Antioxidantes/farmacologia , Desenvolvimento Fetal/efeitos dos fármacos , Hipóxia/tratamento farmacológico , Miócitos Cardíacos/fisiologia , Placenta/fisiologia , Animais , Células Cultivadas , Meios de Cultivo Condicionados , Feminino , Masculino , Compostos Organofosforados/farmacologia , Estresse Oxidativo , Gravidez , Ratos , Ratos Sprague-Dawley , Ubiquinona/análogos & derivados , Ubiquinona/farmacologiaRESUMO
The Developmental Origins of Health and Disease (DOHaD) theory states that a sub-optimal prenatal and early postnatal environment during development leads to an increased risk of long-term development of adult chronic diseases. Developmental programming of disease has the potential to greatly impact the health of our population. Therefore, research has focused on the development of primary treatment strategies and/or therapeutic interventions for individuals who are at increased risk, with the objective to reverse or prevent later life onset of chronic disease in the offspring born from complicated pregnancies. Many studies have focused on systemic treatments and/or interventions in complicated pregnancies to improve offspring outcomes. However, there are limitations to systemic maternal/prenatal treatments, as most of the treatments are able to cross the placenta and have potential adverse off-target effects on the developing fetus. The placenta serves as the primary interface between mother and fetus, and placental dysfunction in complicated pregnancies has been associated with impaired fetal development and negative impact on offspring health. Therefore, recent research has focused on treatment strategies that specifically target the placenta to improve placental function and prevent passage of prenatal therapeutics and/or treatments into the fetal circulation, thus avoiding any potential adverse off-target effects on the fetus. This article reviews the currently available knowledge on treatment strategies and/or therapeutics that specifically target the placenta with the goal of improving pregnancy outcomes with a focus on long-term health of the offspring born of complicated pregnancies.
Assuntos
Desenvolvimento Fetal/efeitos dos fármacos , Terapia Genética , Placenta/efeitos dos fármacos , Complicações na Gravidez/terapia , Animais , Portadores de Fármacos , Composição de Medicamentos , Feminino , Técnicas de Transferência de Genes , Terapia Genética/efeitos adversos , Humanos , Exposição Materna , Troca Materno-Fetal/efeitos dos fármacos , Placenta/fisiopatologia , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/genética , Complicações na Gravidez/fisiopatologia , Efeitos Tardios da Exposição Pré-NatalRESUMO
Syncytiotrophoblast extracellular vesicles (STBEVs), released into the maternal circulation during pregnancy, have been shown to affect vascular function; however, the mechanism remains unknown. In rats, STBEVs were shown to reduce endothelium-mediated vasodilation via lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a multi-ligand scavenger receptor that has been associated with vascular dysfunction. Recently, LOX-1 was shown to interact with the angiotensin II type 1 receptor (AT-1). We hypothesized that, in pregnant mice, STBEVs would impair vascular function via LOX-1 and would specifically affect angiotensin II responses. Uterine arteries from pregnant control (C57BL/6) and LOX-1 knockout (LOX-1KO) mice were isolated on gestational day (GD) 18.5. Endothelium-dependent (methylcholine (MCh); ± N(G)-Nitro-L-arginine methyl ester to assess nitric oxide (NO) contribution), and -independent (sodium nitroprusside) vasodilation, and vasoconstriction (angiotensin II; ± AT-1 [candesartan] or angiotensin II type 2 receptor (AT-2) [PD123.319] receptor antagonists; high potassium salt solution) responses were assessed using wire myography. AT-1 and AT-2 expression was analyzed using fluorescence microscopy. Human umbilical vein endothelial cells (HUVECs) were stimulated with STBEVs ± LOX-1 blocking antibody, and superoxide and peroxynitrite production were analyzed. Although MCh-induced vasodilation was decreased (P=0.0012), NO contribution to vasodilation was greater in LOX-1KO mice (P=0.0055). STBEVs delayed angiotensin II tachyphylaxis in arteries from control but not LOX-1KO mice (P<0.0001), while AT-1 and AT-2 expression was unchanged. STBEVs increased peroxynitrite production in HUVECs via LOX-1 (P=0.0091). In summary, LOX-1 deletion altered endothelium-mediated vasodilation, suggesting that LOX-1 contributes to vascular adaptations in pregnancy. STBEVs increased angiotensin II responsiveness and oxidative stress levels via LOX-1, suggesting that increased LOX-1 expression/activation or STBEVs could adversely affect vascular function and contribute to vascular complications of pregnancy.
Assuntos
Células Endoteliais/metabolismo , Vesículas Extracelulares/metabolismo , Comunicação Parácrina , Receptores Depuradores Classe E/metabolismo , Trofoblastos/metabolismo , Artéria Uterina/metabolismo , Vasoconstrição , Vasodilatação , Adulto , Animais , Células Endoteliais/efeitos dos fármacos , Feminino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo , Ácido Peroxinitroso/metabolismo , Gravidez , Receptores de Angiotensina/metabolismo , Receptores Depuradores Classe E/deficiência , Receptores Depuradores Classe E/genética , Transdução de Sinais , Superóxidos/metabolismo , Artéria Uterina/citologia , Artéria Uterina/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologiaRESUMO
BACKGROUND: Prenatal hypoxia, a common pregnancy complication, leads to impaired cardiovascular outcomes in the adult offspring. It results in impaired vasodilation in coronary and mesenteric arteries of the adult offspring, due to reduced nitric oxide (NO). Thromboxane A2 (TxA2) is a potent vasoconstrictor increased in cardiovascular diseases, but its role in the impact of prenatal hypoxia is unknown. To prevent the risk of cardiovascular disease by prenatal hypoxia, we have tested a maternal treatment using a nanoparticle-encapsulated mitochondrial antioxidant (nMitoQ). We hypothesized that prenatal hypoxia enhances vascular TxA2 responses in the adult offspring, due to decreased NO modulation, and that this might be prevented by maternal nMitoQ treatment. METHODS: Pregnant Sprague-Dawley rats received a single intravenous injection (100 µL) of vehicle (saline) or nMitoQ (125 µmol/L) on gestational day (GD)15 and were exposed to normoxia (21% O2) or hypoxia (11% O2) from GD15 to GD21 (term = 22 days). Coronary and mesenteric arteries were isolated from the 4-month-old female and male offspring, and vasoconstriction responses to U46619 (TxA2 analog) were evaluated using wire myography. In mesenteric arteries, L-NAME (pan-NO synthase (NOS) inhibitor) was used to assess NO modulation. Mesenteric artery endothelial (e)NOS, and TxA2 receptor expression, superoxide, and 3-nitrotyrosine levels were assessed by immunofluorescence. RESULTS: Prenatal hypoxia resulted in increased U46619 responsiveness in coronary and mesenteric arteries of the female offspring, and to a lesser extent in the male offspring, which was prevented by nMitoQ. In females, there was a reduced impact of L-NAME in mesenteric arteries of the prenatal hypoxia saline-treated females, and reduced 3-nitrotyrosine levels. In males, L-NAME increased U46619 responses in mesenteric artery to a similar extent, but TxA2 receptor expression was increased by prenatal hypoxia. There were no changes in eNOS or superoxide levels. CONCLUSIONS: Prenatal hypoxia increased TxA2 vasoconstrictor capacity in the adult offspring in a sex-specific manner, via reduced NO modulation in females and increased TP expression in males. Maternal placental antioxidant treatment prevented the impact of prenatal hypoxia. These findings increase our understanding of how complicated pregnancies can lead to a sex difference in the programming of cardiovascular disease in the adult offspring.
Prenatal hypoxia, when the fetus does not receive enough oxygen, is a common problem during pregnancy that impacts the developing fetus. It is associated with an increased risk of cardiovascular disease in the offspring in adulthood. While the mechanisms are not fully understood, the blood vessel function in the offspring may be impacted by prenatal hypoxia. We hypothesize that prenatal hypoxia increases the constriction of the blood vessels in the offspring. The placenta, an essential organ for fetal development, supplies oxygen and nutrients to the fetus. In prenatal hypoxia pregnancies, the placenta does not work properly. We have been studying a placental treatment (called nMitoQ) to improve placenta function and thereby the blood vessel function of the offspring. We used a rat model of prenatal hypoxia, where pregnant rats (dams) were placed in a low oxygen environment (hypoxia) during the last trimester of pregnancy. Control rats were kept in normal oxygen conditions. The dams were treated with nMitoQ, or with saline (control). Next, we studied the blood vessels of the offspring in adulthood. We found that prenatal hypoxia increases the constriction of the blood vessels, which was prevented by treating the dams with nMitoQ. Interestingly, this impact was more severe in females compared to males, and the mechanisms were different between the sexes. This study helps in the understanding of how complicated pregnancies can impair cardiovascular health in the offspring, and in a potential development of targeted and sex-specific therapies for those offspring at high risk for future cardiovascular disease.
Assuntos
Efeitos Tardios da Exposição Pré-Natal , Ratos Sprague-Dawley , Caracteres Sexuais , Tromboxano A2 , Vasoconstrição , Animais , Feminino , Gravidez , Vasoconstrição/efeitos dos fármacos , Masculino , Tromboxano A2/metabolismo , Antioxidantes/farmacologia , Óxido Nítrico/metabolismo , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Ratos , Hipóxia/metabolismo , Hipóxia Fetal/metabolismo , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologiaRESUMO
Advanced maternal age (≥35 years) is associated with an increased risk of pregnancy complications such as fetal growth restriction and preeclampsia. We previously demonstrated poor pregnancy outcomes (reduced fetal body weight), altered vascular function, and increased expression of endoplasmic reticulum (ER) stress markers (phospho-eIF2α and CHOP) in mesenteric arteries from a rat model of advanced maternal age. Further, treatment of aged dams during pregnancy with an ER stress inhibitor, tauroursodeoxycholic acid (TUDCA) increased fetal body weight (both male and female), tended to improve uterine artery function, and reduced expression of phospho-eIF2α and CHOP in systemic arteries. Placental ER stress has been linked to poor pregnancy outcomes in complicated pregnancies but whether placental ER stress is evident in advanced maternal age is not known. In addition, sex-specific changes in the placental labyrinth and junctional zones from male and female offspring in advanced maternal age have not been investigated. Therefore, the current study aimed to investigate the effect of TUDCA intervention on placental ER stress. We hypothesize that placental ER stress is increased in a rat model of advanced maternal age that is alleviated by TUDCA intervention for both sexes. Placental ER stress markers (GRP78, phospho-eIF2α, ATF-4, CHOP, ATF-6α, and sXBP-1) were quantified by Western blot in placentas from male and female offspring; the labyrinth and junction zones were analyzed separately. In the placental labyrinth zone from male offspring, only GRP78 (p = 0.007) was increased in aged dams compared to young dams; TUDCA treatment reduced the placental expression of GRP78 in aged dams (p = 0.003). In addition, TUDCA reduced the levels of phospho-eIF2α (p = 0.021), ATF-4 (p = 0.016), and CHOP (p = 0.012) in aged dams but no effect was observed in young TUDCA-treated dams. In the placental labyrinth zone from female offspring, an increased level of phospho-eIF2α (p = 0.005) was observed in aged dams compared to young dams, and TUDCA treatment had no effect in both young and aged groups. In the placental junctional zone from male and female offspring, no changes in the expression of GRP78, phospho-eIF2α, ATF-4, CHOP, and ATF-6α was observed with or without TUDCA treatment in both young and aged groups, however, a reduced expression of sXBP-1 protein was observed in from both male (p = 0.001) and female (p = 0.031) placentas from aged-TUDCA treated dams compared to aged control. In conclusion, our data highlight the complexity and sex-specificity of ER stress responses in advanced maternal age with TUDCA treatment maintaining ER stress proteins to basal levels and improving fetal growth in both male and female offspring.
Assuntos
Peso Fetal , Placenta , Ratos , Gravidez , Feminino , Masculino , Animais , Placenta/metabolismo , Idade Materna , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático , Resultado da Gravidez , Retículo EndoplasmáticoRESUMO
Gestational hypoxia is a major contributor to fetal growth restriction (FGR) and perinatal morbidity and mortality and has been closely linked to the activation of the unfolded protein response (UPR) in the placenta. Recent studies on adverse pregnancy conditions show differential adaptive responses in pregnancies carrying male or female fetuses. Here, we use an established rat model of hypoxic pregnancy and FGR to test the hypothesis that chronic hypoxia promotes sexually dimorphic activation of the placental UPR. Our data showed that gestational hypoxia increased glucose regulatory protein 78 (GRP78) expression in male placentae, increased activating transcription factor 6 activation (ATF6) in female placentae, and did not induce changes in other UPR markers. In addition, gestational hypoxia reduced fetal weight only in males and ATF6 activation correlated with an increase in the fetal crown-rump-length/body weight ratio only in females. These results suggest sex-specific divergence in the placental adaptive response to gestational hypoxia, which may account for the sexual dimorphism observed in placental function and pregnancy outcomes in complicated pregnancies.
Assuntos
Placenta , Complicações na Gravidez , Humanos , Gravidez , Feminino , Masculino , Ratos , Animais , Placenta/metabolismo , Roedores , Caracteres Sexuais , Resultado da Gravidez , Retardo do Crescimento Fetal/metabolismo , Resposta a Proteínas não Dobradas , Complicações na Gravidez/metabolismo , Hipóxia/metabolismoRESUMO
BACKGROUND: Preeclampsia is a complex syndrome that includes maternal vascular dysfunction. Syncytiotrophoblast-derived extracellular vesicles from preeclampsia placentas (preeclampsia-STBEVs) were shown to induce endothelial dysfunction, but an endothelial transmembrane mediator is still unexplored. The LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1) is a transmembrane scavenger receptor that can cause endothelial dysfunction, and its expression is increased in the endothelium of preeclampsia women. In this study, we hypothesized that LOX-1 mediates the effects of preeclampsia-STBEVs on endothelial function. METHODS: Preeclampsia-STBEVs were collected by perfusion of placentas from women with preeclampsia and in vitro and ex vivo endothelial cell function were assessed. RESULTS: In human umbilical vein endothelial cells, inhibition of LOX-1 with LOX-1 blocking antibody (TS20) reduced the uptake of preeclampsia-STBEVs (61.3±8.8%). TS20 prevented the activation of ERK (extracellular signal-regulated kinase, a kinase downstream of LOX-1) and reduced the activation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells; 21.1±8.0%) and nitrative stress (23.2±10.3%) that was induced by preeclampsia-STBEVs. Vascular function was assessed by wire myography in isolated mesenteric arteries from pregnant rats that were incubated overnight with preeclampsia-STBEVs±TS20. TS20 prevented endothelium-dependent vasodilation impairment induced by preeclampsia-STBEVs. Nitric oxide contribution to the relaxation was reduced by preeclampsia-STBEVs, which was prevented by TS20. Superoxide dismutase or apocynin, an inhibitor of NOX (nicotinamide adenine dinucleotide phosphate oxidase), restored the impaired endothelium-dependent vasodilation in arteries exposed to preeclampsia-STBEVs. CONCLUSIONS: Taken together, our findings demonstrate that LOX-1 mediates the endothelial dysfunction induced by preeclampsia-STBEVs. Our study further expands on the mechanisms that may lead to adverse outcomes in preeclampsia and proposes LOX-1 as a potential target for future interventions.
Assuntos
Vesículas Extracelulares , Pré-Eclâmpsia , Doenças Vasculares , Gravidez , Humanos , Feminino , Animais , Ratos , Células Endoteliais , Endotélio , Receptores de LDL Oxidado , LectinasRESUMO
Advanced maternal age (≥35 years) is a risk factor for poor pregnancy outcomes. Pregnancy requires extensive maternal vascular adaptations, and with age, our blood vessels become stiffer and change in structure (collagen and elastin). However, the effect of advanced maternal age on the structure of human resistance arteries during pregnancy is unknown. As omental resistance arteries contribute to blood pressure regulation, assessing their structure in pregnancy may inform on the causal mechanisms underlying pregnancy complications in women of advanced maternal age. Omental fat biopsies were obtained from younger (<35 years) or advanced maternal age (≥35 years) women during caesarean delivery (n = 7-9/group). Arteries (200-300 µm) were isolated and passive mechanical properties (circumferential stress and strain) assessed with pressure myography. Collagen (Masson's Trichrome) and elastin (Verhoff) were visualized histologically and % positively-stained area was assessed. Median maternal age was 32 years (range 25-34) for younger, and 38 years (range 35-42) for women of advanced maternal age. Circumferential strain was lower in arteries from advanced maternal age versus younger women but circumferential stress was not different. Omental artery collagen levels were similar, while elastin levels were lower with advanced maternal age versus younger pregnancies. The collagen:elastin ratio was greater in arteries from advanced maternal age versus younger women. In conclusion, omental arteries from women of advanced maternal age were less compliant with less elastin compared with arteries of younger controls, which may affect how vascular stressors are tolerated during pregnancy. Understanding how vascular aging affects pregnancy adaptations may contribute to better pregnancy outcomes.
Assuntos
Elastina , Gestantes , Humanos , Feminino , Gravidez , Adulto , Idade Materna , Elastina/farmacologia , Artérias , Resultado da Gravidez , ColágenoRESUMO
Advanced maternal age (≥35 years) increases the risk of vascular complications in pregnancy that can result in fetal growth restriction and preeclampsia. Endoplasmic reticulum (ER) stress has been linked to adverse pregnancy outcomes in these complicated pregnancies. However, the role of ER stress in advanced maternal age is not known. We hypothesize that increased ER stress contributes to altered vascular function and poor pregnancy outcomes, and that treatment with the ER-stress inhibitor TUDCA will improve pregnancy outcomes. First, young and aged non-pregnant/pregnant rats were used to assess ER stress markers in mesenteric arteries; mesenteric artery phospho-eIF2α and CHOP expression were increased in aged dams compared to young dams. In a second study, young and aged control and TUDCA-treated dams were studied on gestational day (GD) 20 (term = 22 days). TUDCA treatment was provided via the drinking water throughout pregnancy (GD0-GD20; calculated dose of 150 mg/kg/day TUDCA). ER stress markers were quantified in mesenteric arteries, blood pressure was measured, pregnancy outcomes were recorded, mesenteric and main uterine arteries were isolated and vascular function was assessed by wire myography. Aged dams had increased phospho-eIF2α and CHOP expression, reduced fetal weight, reduced litter size, and impaired uterine artery relaxation. In the aged dams, TUDCA treatment reduced phospho-eIF2α and CHOP expression, reduced blood pressure, improved fetal body weight, and tended to improve uterine artery function compared to control-treated aged dams. In conclusion, our data illustrate the role of ER stress, as well as TUDCA as a potential therapeutic that may benefit pregnancy outcomes in advanced maternal age.
RESUMO
Exposome research aims to comprehensively understand the multiple environmental exposures that influence human health. To date, much of exposome science has focused on environmental chemical exposures and does not take a lifecourse approach. The rising prevalence of obesity, and the limited success in its prevention points to the need for a better understanding of the diverse exposures that associate with, or protect against, this condition, and the mechanisms driving its pathogenesis. The objectives of this review were to 1. evaluate the evidence on the maternal metabolic exposome in the programming of offspring growth/obesity and 2. identify and discuss the mechanisms underlying the programming of obesity. A systematic review was conducted following PRISMA guidelines to capture articles that investigated early life metabolic exposures and offspring weight and/or obesity outcomes. Scientific databases were searched using pre-determined indexed search terms, and risk of bias assessments were conducted to determine study quality. A final total of 76 articles were obtained and extracted data from human and animal studies were visualised using GOfER diagrams. Multiple early life exposures, including maternal obesity, diabetes and adverse nutrition, increase the risk of high weight at birth and postnatally, and excess adipose accumulation in human and animal offspring. The main mechanisms through which the metabolic exposome programmes offspring growth and obesity risk include epigenetic modifications, altered placental function, altered composition of the gut microbiome and breast milk, and metabolic inflammation, with downstream effects on development of the central appetite system, adipose tissues and liver. Understanding early life risks and protectors, and the mechanisms through which the exposome modifies health trajectories, is critical for developing and applying early interventions to prevent offspring obesity later in life.