scholarly journals Altered Vascular Adaptations to Pregnancy in a Rat Model of Advanced Maternal Age

2021 ◽  
Vol 12 ◽  
Author(s):  
Mazhar Pasha ◽  
Amy L. Wooldridge ◽  
Raven Kirschenman ◽  
Floor Spaans ◽  
Sandra T. Davidge ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Rat Model ◽  
Vascular Function ◽  
Maternal Age ◽  
Advanced Maternal Age ◽  
Mesenteric Arteries ◽  
Compensatory Mechanism ◽  
Aged Rats ◽  
Pregnant Rats

Advanced maternal age (≥35 years old) increases the risk of pregnancy complications such as preeclampsia and fetal growth restriction. We previously demonstrated vascular dysfunction and abnormal pregnancy outcomes in a rat model of advanced maternal age. However, vascular adaptations to pregnancy in aging were not studied. We hypothesize that advanced maternal age is associated with a more vasoconstrictive phenotype due to reduced nitric oxide (NO) and increased activity of matrix metalloproteinases (MMPs), contributing to impaired vascular adaptations to pregnancy. A rat model of advanced maternal age was used: young (4 months) and aged (9.5 months; ∼35 years in humans) non-pregnant and pregnant rats. On gestational day 20 (term = 22 days; non-pregnant rats were aged-matched), blood pressure and heart rate were measured (tail cuff plethysmography) and vascular function was assessed in mesenteric arteries (wire myography). Endothelium-dependent relaxation to methylcholine (MCh) was assessed in the presence/absence of nitric oxide synthase inhibitor (L-NAME), or inhibitors of endothelium-dependent hyperpolarization (EDH; apamin and TRAM-34). Vasoconstriction responses to big endothelin-1 (bigET-1), in the presence/absence of MMPs-inhibitor (GM6001) or endothelin converting enzyme (ECE-1) inhibitor (CGS35066), in addition, ET-1 responsiveness, were measured. Blood pressure was elevated only in aged non-pregnant rats (p < 0.001) compared to all other groups. MCh responses were not different, however, L-NAME decreased maximum vasodilation in young (p < 0.01) and aged pregnant rats (p < 0.001), and decreased MCh sensitivity in young non-pregnant rats (p < 0.01), without effects in aged non-pregnant rats. EDH contribution to relaxation was similar in young non-pregnant, and aged non-pregnant and pregnant rats, while EDH-mediated relaxation was absent in young pregnant rats (p < 0.001). BigET-1 responses were enhanced in aged non-pregnant (p < 0.01) and pregnant rats (p < 0.05). No significant changes in bigET-1 conversion occurred in the presence of MMP-inhibitor, whereas ECE-1 inhibition reduced bigET-1 constriction in aged rats (p < 0.01). No differences in ET-1 sensitivity were observed. In conclusion, contrary to our hypothesis, reduced blood pressure, and an increased EDH-dependent contribution to vasodilation suggest a compensatory mechanism that may reflect beneficial adaptations in these aged rats that were able to maintain pregnancy. These data increase our understanding of how the vascular adaptive pathways in pregnancy compensate for advanced maternal age.

scholarly journals Nitric oxide synthase-mediated blood pressure regulation in obese melanocortin-4 receptor-deficient pregnant rats

2016 ◽  
Vol 311 (5) ◽  
pp. R851-R857 ◽  
Author(s):  
Frank T. Spradley ◽  
Jennifer M. Sasser ◽  
Jacqueline B. Musall ◽  
Jennifer C. Sullivan ◽  
Joey P. Granger
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Mesenteric Arteries ◽  
Elevated Blood Pressure ◽  
Pressure Regulation ◽  
Elevated Blood ◽  
Pregnant Rats ◽  
Melanocortin 4 Receptor ◽  
Regulation Of Blood Pressure

Although obesity increases the risk for hypertension in pregnancy, the mechanisms responsible are unknown. Increased nitric oxide (NO) production results in vasodilation and reduced blood pressure during normal pregnancy in lean rats; however, the role of NO is less clear during obese pregnancies. We examined the impact of obesity on NO synthase (NOS)-mediated regulation of blood pressure during pregnancy by testing the hypothesis that NOS activity, expression, and regulation of vascular tone and blood pressure are reduced in obese pregnant rats. At gestational day 19, melanocortin-4 receptor (MC4R)-deficient obese rats (MC4R) had greater body weight and fat mass with elevated blood pressure and circulating sFlt-1 levels compared with MC4R pregnant rats. MC4R pregnant rats also had less circulating cGMP levels and reduced total NOS enzymatic activity and expression in mesenteric arteries. Despite decreased biochemical measures of NO/NOS in MC4R rats, NOS inhibition enhanced vasoconstriction only in mesenteric arteries from MC4R rats, suggesting greater NOS-mediated tone. To examine the role of NOS on blood pressure regulation in obese pregnant rats, MC4R and MC4R pregnant rats were administered the nonselective NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME, 100 mg/l) from gestational day 14 to 19 in drinking water. The degree by which l-NAME raised blood pressure was similar between obese and lean pregnant rats. Although MC4R obese pregnant rats had elevated blood pressure associated with reduced total NOS activity and expression, they had enhanced NOS-mediated attenuation of vasoconstriction, with no evidence of alterations in NOS-mediated regulation of blood pressure.

scholarly journals Altered vascular contractility in adult female rats with hypertension programmed by prenatal glucocorticoid exposure

2006 ◽  
Vol 188 (3) ◽  
pp. 435-442 ◽  
Author(s):  
P W F Hadoke ◽  
R S Lindsay ◽  
J R Seckl ◽  
B R Walker ◽  
C J Kenyon
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Adult Female ◽  
Vascular Function ◽  
Mesenteric Arteries ◽  
Female Rats ◽  
Control Group ◽  
Pregnant Rats ◽  
Vascular Contractility

Excessive exposure to glucocorticoids during gestation reduces birth weight and induces permanent hypertension in adulthood. The mechanisms underlying this programmed elevation of blood pressure have not been established. We hypothesised that prenatal glucocorticoid exposure may lead to vascular dysfunction in adulthood. Pregnant rats received dexamethasone (Dex) (100 μg/kg, s.c.) or vehicle (control) daily throughout pregnancy. Blood pressure was elevated (students t-test, unpaired; P < 0.05) in adult female offspring (aged 12–16 weeks) of Dex-treated mothers (148.0 ± 3.6 mmHg, n=10) compared with the control group (138.0 ± 2.5 mmHg, n=8). Vascular responsiveness in aortae and mesenteric arteries was differentially affected by prenatal Dex: aortae were less responsive to angiotensin II, whereas mesenteric arteries were more responsive to norepinephrine, vasopressin and potassium (mesenteric arteries respond poorly to angiotensin II in vitro). Acetylcholine-mediated, endothelium-dependent relaxation was similar in both groups. Prenatal exposure to Dex had no effect on blood pressure or aldosterone response to acute (15 min, i.v.) infusion of angiotensin II (75 ng/kg per min). In contrast, chronic (2-week, s.c.) infusion of angiotensin II (100 ng/kg per min) produced a greater elevation (P < 0.05) of blood pressure in Dex-treated rats (150.0 ± 3.6 mmHg) than in controls (135.3 ± 5.4 mmHg), and aldosterone levels were higher in Dex-treated animals. There was no angiotensin II-induced medial hypertrophy/hyperplasia in mesenteric arteries from Dex-treated rats. These results indicate that vascular function is altered in a region-specific manner in rats with glucocorticoid-programmed hypertension. Despite a striking increase in mesenteric artery contraction in Dex-treated rats, in vivo studies suggest that abnormalities of the renin-angiotensin-aldosterone system, rather than enhanced vascular contractility, may be responsible for the elevation of blood pressure in these animals.

scholarly journals Maternal vascular responses to hypoxia in a rat model of intrauterine growth restriction

2016 ◽  
Vol 311 (6) ◽  
pp. R1068-R1075 ◽  
Author(s):  
Mais M. Aljunaidy ◽  
Jude S. Morton ◽  
Christy-Lynn Cooke ◽  
Sandra T. Davidge
Keyword(s):  
Blood Pressure ◽  
Rat Model ◽  
Intrauterine Growth Restriction ◽  
Vascular Function ◽  
Uterine Artery ◽  
Resistance Index ◽  
Maternal Blood ◽  
Pregnant Rats ◽  
Intrauterine Growth ◽  
Maternal Blood Pressure

Intrauterine growth restriction (IUGR) is a common pregnancy complication and is a leading cause of fetal morbidity and mortality. Placental hypoxia contributes to adverse fetal consequences, such as IUGR. Exposing pregnant rats to hypoxia can lead to IUGR; however, assessment of maternal vascular function in a rat model of hypoxia, and the mechanisms that may contribute to adverse pregnancy outcomes, has not been extensively studied. We hypothesized that exposing pregnant rats to hypoxia will affect maternal systemic vascular function and increase the uterine artery resistance index (RI), which will be associated with IUGR. To test this hypothesis, pregnant rats were kept in normoxia (21% O2) or hypoxia (11% O2) from gestational day (GD) 6 to 20. Maternal blood pressure, uteroplacental resistance index (RI) (ultrasound biomicroscopy), and vascular function (wire myography) were assessed in uterine and mesenteric arteries. Fetal weight was significantly reduced ( P < 0.001), while maternal blood pressure was increased ( P < 0.05) in rats exposed to hypoxia. Maternal vascular function was also affected after exposure to hypoxia, including impaired endothelium-dependent vasodilation responses to methacholine in isolated uterine arteries (pEC50 normoxia: 6.55 ± 0.23 vs. hypoxia: 5.02 ± 0.35, P < 0.01) and a reduced uterine artery RI in vivo (normoxia: 0.63 ± 0.04 vs. hypoxia: 0.53 ± 0.01, P < 0.05); associated with an increase in umbilical vein RI (normoxia: 0.35 ± 0.02 vs. hypoxia: 0.45 ± 0.04, P < 0.05). These data demonstrate maternal and fetal alterations in vascular function due to prenatal exposure to hypoxia. Further, although there was a compensatory reduction in uterine artery RI in the hypoxia groups, this was not sufficient to prevent IUGR.

scholarly journals Maternal food restriction in the second half of pregnancy affects vascular function but not blood pressure of rat female offspring

1999 ◽  
Vol 81 (1) ◽  
pp. 73-80 ◽  
Author(s):  
Kathleen Holemans ◽  
Robert Gerber ◽  
Kris Meurrens ◽  
Fred De Clerck ◽  
Lucilla Poston ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Growth Retardation ◽  
Vascular Function ◽  
Food Restriction ◽  
Female Offspring ◽  
Normal Diet ◽  
Mesenteric Arteries ◽  
Pregnant Rats

Food restriction during pregnancy in rats induces intrauterine growth retardation with consequences persisting into adulthood. In the present study we have investigated the hypothesis that malnutrition in pregnant rats may lead to altered cardiovascular function in adult female offspring. Perinatal growth retardation was induced by a 50 % reduction of normal dietary intake in rats during the second half of pregnancy. Systolic and diastolic blood pressure values and heart rate were recorded in conscious female offspring (100 d old) using a femoral artery probe. No significant differences in heart rate, or in systolic and diastolic blood pressures were recorded between control offspring and offspring of nutritionally deprived rats. In order to ascertain whether cardiovascular variables in the offspring were influenced by lactation, subgroups of offspring from food-restricted dams were fostered with lactating dams fed on a normal diet. Blood pressure and heart rate were also found to be normal in these offspring. The rise in blood pressure associated with NO inhibition was similar in all groups. Isolated resistance artery function was assessed in vitro in offspring (100–120 d old) of a second group of semi-starved dams. Small mesenteric arteries from these animals showed reduced endothelium-dependent relaxation (to acetylcholine and bradykinin), but enhanced sensitivity to exogenous NO (sodium nitroprusside). We conclude that food restriction during the second half of pregnancy and/or lactation does not induce hypertension in adult offspring, but may effect subtle changes in vascular function.

scholarly journals Abnormal nitric oxide production in aged rat mesenteric arteries is mediated by NAD(P)H oxidase-derived peroxide

2009 ◽  
Vol 297 (6) ◽  
pp. H2227-H2233 ◽  
Author(s):  
Xiaosun Zhou ◽  
H. Glenn Bohlen ◽  
Joseph L. Unthank ◽  
Steven J. Miller
Keyword(s):  
Nitric Oxide ◽  
Vascular Function ◽  
Spontaneously Hypertensive Rat ◽  
Oxidant Stress ◽  
Mesenteric Arteries ◽  
No Production ◽  
Aged Rats ◽  
Wistar Kyoto Rats ◽  
Wistar Kyoto

Previous work in our laboratory showed increased basal periarterial nitric oxide (NO) and H2O2 concentrations in the spontaneously hypertensive rat, characterized by oxidant stress, as well as impaired flow-mediated NO production that was corrected by a reduction of periarterial H2O2. Aging is also associated with an increase in vascular reactive oxygen species and results in abnormal vascular function. The current study was designed to assess the role of H2O2 in regulating NO production during vascular aging. In vivo, real-time NO and H2O2 concentrations were measured by microelectrodes in mesenteric arteries of retired breeder (aged; 8–12 mo) and young (2 to 3 mo) Wistar-Kyoto rats under conditions of altered flow. The results in aged rats revealed elevated basal NO (1,611 ± 286 vs. 793 ± 112 nM, P < 0.05) and H2O2 concentrations (16 ± 2 vs. 9 ± 1 μM, P < 0.05) and a flow-mediated increase in H2O2 but not NO production. Pretreatment of aged rats with the antioxidant apocynin lowered both basal H2O2 (8 ± 1 μM) and NO (760 ± 102 nM) to young levels and restored flow-mediated NO production. Similar results were obtained with the NAD(P)H oxidase inhibitor gp91ds-tat. In addition, acute incubation with topical polyethylene-glycolated catalase lowered the baseline NO concentration and restored flow-mediated NO production. Taken together, the data indicate that elevated baseline and suppressed flow-mediated NO production in aged Wistar-Kyoto rats are mediated by NAD(P)H oxidase-derived H2O2.

Effect of Advanced Maternal Age on Pregnancy Outcomes and Vascular Function in the Rat

Hypertension ◽  
2015 ◽  
Vol 65 (6) ◽  
pp. 1324-1330 ◽  
Author(s):  
Alison S. Care ◽  
Stephane L. Bourque ◽  
Jude S. Morton ◽  
Emma P. Hjartarson ◽  
Sandra T. Davidge
Keyword(s):  
Pregnancy Outcomes ◽  
Vascular Function ◽  
Maternal Age ◽  
Advanced Maternal Age

Regulation of renal CYP4A expression and 20-HETE synthesis by nitric oxide in pregnant rats

2003 ◽  
Vol 285 (2) ◽  
pp. F295-F302 ◽  
Author(s):  
Mong-Heng Wang ◽  
Jishi Wang ◽  
Hsin-Hsin Chang ◽  
Barbara A. Zand ◽  
Miao Jiang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Rat Kidney ◽  
Late Pregnancy ◽  
Inhibitory Effect ◽  
Female Rats ◽  
Male Rats ◽  
Pregnant Rats ◽  
Renal Vasoconstriction ◽  
Dependent Inhibition

20-Hydroxyeicosatetraenoic acid (20-HETE), which promotes renal vasoconstriction, is formed in the rat kidney primarily by cytochrome P-450 (CYP) 4A isoforms (4A1, 4A2, 4A3, 4A8). Nitric oxide (NO) has been shown to bind to the heme moiety of the CYP4A2 protein and to inhibit 20-HETE synthesis in renal arterioles of male rats. However, it is not known whether NO interacts with and affects the activity of CYP4A1 and CYP4A3, the major renal CYP4A isoforms in female rats. Incubation of recombinant CYP4A1 and 4A3 proteins with sodium nitroprusside (SNP) shifted the absorbance at 440 nm, indicating the formation of a ferric-nitrosyl-CYP4A complex. The absorbance for CYP4A3 was about twofold higher than that of CYP4A1. Incubation of SNP or peroxynitrite (PN; 0.01–1 mM) with CYP4A recombinant membranes caused a concentration-dependent inhibition of 20-HETE synthesis, with both chemicals having a greater inhibitory effect on CYP4A3-catalyzed activity. Moreover, incubation of CYP4A1 and 4A3 proteins with PN (1 mM) resulted in nitration of tyrosine residues in both proteins. In addition, PN and SNP inhibited 20-HETE synthesis in renal microvessels from female rats by 65 and 59%, respectively. We previously showed that microvessel CYP4A1/CYP4A3 expression and 20-HETE synthesis are decreased in late pregnancy. Therefore, we investigated whether such a decrease is dependent on NO, the synthesis of which has been shown to increase in late pregnancy. Administration of NG-nitro-l-arginine methyl ester (l-NAME) to pregnant rats for 6 days ( days 15- 20 of pregnancy) caused a significant increase in systolic blood pressure, which was prevented by concurrent treatment with the CYP4A inhibitor 1-aminobenzotriazole (ABT). Urinary NO2/NO3 excretion decreased by 40 and 52% in l-NAME- and l-NAME + ABT-treated groups, respectively. Interestingly, renal microvessel 20-HETE synthesis showed a marked increase following l-NAME treatment, and this increase was diminished with coadministration of ABT. These results demonstrate that NO interacts with CYP4A proteins in a distinct manner and it interferes with renal microvessel 20-HETE synthesis, which may play an important role in the regulation of blood pressure and renal function during pregnancy.

Renal and cardiac oxidative/nitrosative stress in salt-loaded pregnant rat

2007 ◽  
Vol 293 (4) ◽  
pp. R1657-R1665 ◽  
Author(s):  
Annie Beauséjour ◽  
Véronique Houde ◽  
Karine Bibeau ◽  
Rébecca Gaudet ◽  
Jean St-Louis ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Nitrosative Stress ◽  
Gestational Hypertension ◽  
Sodium Intake ◽  
Pregnant Rats ◽  
High Sodium ◽  
High Sodium Intake ◽  
Arterial Blood ◽  
Cardiac Ventricle

Sodium supplementation given for 1 wk to nonpregnant rats induces changes that are adequate to maintain renal and circulatory homeostasis as well as arterial blood pressure. However, in pregnant rats, proteinuria, fetal growth restriction, and placental oxidative stress are observed. Moreover, the decrease in blood pressure and expansion of circulatory volume, normally associated with pregnancy, are prevented by high-sodium intake. We hypothesized that, in these pregnant rats, a loss of the balance between prooxidation and antioxidation, particularly in kidneys and heart, disturbs the normal course of pregnancy and leads to manifestations such as gestational hypertension. We thus investigated the presence of oxidative/nitrosative stress in heart and kidneys following high-sodium intake in pregnant rats. Markers of this stress [8-isoprostaglandin F2α (8-iso-PGF2α) and nitrotyrosine], producer of nitric oxide [nitric oxide synthases (NOSs)], and antioxidants [superoxide dismutase (SOD) and catalase] were measured. Then, molecules (Na+-K+-ATPase and aconitase) or process [apoptosis (Bax and Bcl-2), inflammation (monocyte chemoattractant protein-1, connective tissue growth factor, and TNF-α)] susceptible to free radicals was determined. In kidneys from pregnant rats on 1.8% NaCl-water, NOSs, apoptotic index, and nitrotyrosine expression were increased, whereas Na+-K+-ATPase mRNA and activity were decreased. In the left cardiac ventricle of these rats, heightened nitrotyrosine, 8-iso-PGF2α, and catalase activity together with reduced endothelial NOS protein expression and SOD and aconitase activities were observed. These findings suggest that oxidative/nitrosative stress in kidney and left cardiac ventricle destabilizes the normal course of pregnancy and could lead to gestational hypertension.

scholarly journals Role of NO in arterial vascular function of intertidal fish (Girella laevifrons) and marine fish (Isacia conceptionis)

2016 ◽  
Vol 76 (2) ◽  
pp. 500-505
Author(s):  
F. A. Moraga ◽  
N. Urriola-Urriola
Keyword(s):  
Nitric Oxide ◽  
Sodium Nitroprusside ◽  
Marine Fish ◽  
Vascular Function ◽  
Isometric Tension ◽  
Mesenteric Arteries ◽  
Response Curves ◽  
Intertidal Fish ◽  
Branchial Arteries

Abstract Previous studies performed in intertidal fish (Girella laevifrons),as well as marine fish (Isacia conceptionis), showed that acetylcholine (ACh) produced contractions mediated by cyclooxygenases that were dependent on the area and potency of contraction in several arterial vessels. Given that the role of nitric oxide is poorly understood in fish, the objective of our study was to evaluate the role of nitric oxide in branchial afferent (ABA), branchial efferent (ABE), dorsal (DA) and mesenteric (MA) arterial vessels from both Girella laevifrons and Isacia conceptionis. We studied afferent and efferent branchial, dorsal and mesenteric arteries that were dissected from 6 juvenile specimens. Isometric tension studies were done using dose response curves (DRC) for Ach (10–13 to 10–3 M) and blockade with L-NAME (10–5 M), and DRC for sodium nitroprusside (SNP, a donor of NO). L-NAME produced an attenuation of the contractile response in the dorsal, afferent and efferent branchial arteries and a potentiation of the contraction in the MA. SNP caused 70% dilation in the mesenteric artery and 40% in the dorsal artery. Our results suggest that Ach promotes precarious dilatation in MA mediated by NO; data that is supported by the use of sodium nitroprusside. In contrast, in the vessels DA, ABA and EBA our results support that the pathway Ach-NO-relaxation is absent in both species.

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