Physiological Remodelling of the Maternal Uterine Circulation during Pregnancy

Mandalà, Maurizio; Osol, George

doi:10.1111/j.1742-7843.2011.00793.x

Cited by 89 publications

(72 citation statements)

References 52 publications

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“…A previous report in the TgA model indicated that contraction to PE was increased compared with SD UA at late gestation (32). Our observation of a similar contraction to PE in intact arteries of SD and TgA UA indicates that this difference appears later in gestation, consistent with the increased sensitivity to ␣-adrenergic stimulation in late pregnancy compared with arteries from nonpregnant animals (27), and may be related to the great degree of remodeling that this vascular bed endures during gestation (22). Contraction to PE was greatly affected by preincubation with indomethacin in TgA, lending further support to an increased role for prostanoids in the local vascular response in TgA UA at early gestation.…”

Section: Discussionsupporting

confidence: 84%

Functional changes in the uterine artery precede the hypertensive phenotype in a transgenic model of hypertensive pregnancy

Pulgar

Yamaleyeva

Varagić

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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The pregnant female human angiotensinogen (hAGN) transgenic rat mated with the male human renin (hREN) transgenic rat is a model of preeclampsia (TgA) with increased blood pressure, proteinuria, and placenta alterations of edema and necrosis at late gestation. We studied vascular responses and the role of COX-derived prostanoids in the uterine artery (UA) at early gestation in this model. TgA UA showed lower stretch response, similar smooth muscle ␣-actin content, and lower collagen content compared with Sprague-Dawley (SD) UA. Vasodilation to acetylcholine was similar in SD and TgA UA (64 Ϯ 8 vs. 75 Ϯ 6% of relaxation, P Ͼ 0.05), with an acetylcholine-induced contraction in TgA UA that was abolished by preincubation with indomethacin (78 Ϯ 6 vs. 83 Ϯ 11%, P Ͼ 0.05). No differences in the contraction to phenylephrine were observed (159 Ϯ 11 vs. 134 Ϯ 12 %KMAX, P Ͼ 0.05), although in TgA UA this response was greatly affected by preincubation with indomethacin (179 Ϯ 16 vs. 134 Ϯ 9 %KMAX, P Ͻ 0.05, pD2 5.92 Ϯ 0.08 vs. 5.85 Ϯ 0.03, P Ͻ 0.05). Endothelium-independent vasodilation was lower in TgA UA (92 Ϯ 2 vs. 74 Ϯ 5% preconstricted tone, P Ͻ 0.05), and preincubation with indomethacin restored the response to normal values (90 Ϯ 3 vs. 84 Ϯ 3%). Immunostaining showed similar signals for ␣-actin, COX-2, and eNOS between groups (P Ͼ 0.05). Plasma thromboxane levels were similar between groups. In summary, TgA UA displays functional alterations at early gestation before the preeclamptic phenotype is established. Inhibition of COX enzymes normalizes some of the functional defects in the TgA UA. An increased role for COX-derived prostanoids in this model of preeclampsia may contribute to the development of a hypertensive pregnancy. preeclampsia; vasodilation; vasoconstriction; cyclooxygenase-2; endothelial nitric oxide synthase PREECLAMPSIA IS A COMMON DISORDER OF PREGNANCY that manifests with hypertension and proteinuria in the last term of pregnancy. It is proposed that hypertensive disorders of pregnancy originate from defective trophoblast invasion and result in vascular endothelial dysfunction triggered by placental ischemia (7). An increased response to vasoconstrictor agonists is characteristic of pregnancies at risk of developing preeclampsia (13).The transgenic female rat containing the human angiotensinogen (hAGN) gene mated with the male transgenic rat containing human renin (hREN) is an established rodent model (TgA) that mimics many features of preeclampsia, including high blood pressure and proteinuria in the last third of gestation, characteristics that are absent in the reverse mating (4). At late gestation, TgA rats display increased circulating and uteroplacental levels of angiotensin II (Ang II), whereas in the reverse mating only uteroplacental Ang II is increased (16). Thus species-specific dependency of renin and angiotensinogen for rodent and human proteins and their localization in the placenta and the circulation form the basis of this model. Increased circulating levels of Ang II may derive from...

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Section: Discussionsupporting

confidence: 84%

Functional changes in the uterine artery precede the hypertensive phenotype in a transgenic model of hypertensive pregnancy

Pulgar

Yamaleyeva

Varagić

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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“…9 In aged dams, maximal constriction of the uterine artery to the α-adrenoceptor agonist phenylephrine was reduced by 21% ( Figure 2A and 2B), albeit sensitivity to phenylephrine was not altered (pEC 50 ; young: 7.5±0.1 versus aged: 7.3±0.1; P=0.12). Maximal constriction to high KCl buffer was reduced by 35% in aged compared with young dams at gestational day 20 (P<0.05; Figure 2C).…”

Section: Uterine Artery Functionmentioning

confidence: 91%

“…Dramatic maternal hemodynamic changes that occur during gestation include an increased blood volume, enhanced cardiac output, and reduced total peripheral resistance. 8 These maternal cardiovascular adaptations enable a progressive increase in blood supply to the placenta (via the uterine artery) 9 to support the increasing demands of the growing fetus throughout gestation. The mechanisms of reduced peripheral vascular resistance during normal pregnancy are not completely understood but include increased bioavailability of endothelial-derived vasodilators, such as nitric oxide (NO) and endothelial-derived hyperpolarization.…”

mentioning

confidence: 99%

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

et al. 2015

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Advanced maternal age is becoming increasingly common in Western societies and is associated with increased maternal and fetal morbidity and mortality. We hypothesized that aging results in impaired vascular function in pregnancy because of increased vascular oxidative stress and resultant scavenging of nitric oxide in both uterine and systemic arteries, causing reduced uteroplacental perfusion and poor pregnancy outcomes. Using aged rats (9.5 months), we investigated the effect of a delayed first natural pregnancy on pregnancy outcomes and uterine and mesenteric artery function on gestational day 20. Delayed pregnancy in the rat reduced fertility by 46%, reduced litter size by 36%, caused fetal growth restriction, increased placental weight, and increased maternal systolic blood pressure (by 16 mm Hg). Uterine arteries from aged dams displayed reduced constriction to phenylephrine (young: 14.3±0.94 mN/mm versus aged: 11.4±0.5 mN/mm, P =0.02) and potassium chloride (124 mmol/L; young: 21.8±1.27 mN/mm versus aged: 14.2±1.7 mN/mm; P =0.01). Methacholine-induced vasodilation was similar in uterine arteries from young and aged dams. However, mesenteric arteries from aged dams had a greater nitric oxide and a reduced endothelial-derived hyperpolarization contribution to methacholine-mediated vasodilation compared with young dams. Both uterine and mesenteric arteries from aged dams had greater active myogenic responses, with area under the curve increased by 228% and 151%, in aged uterine and mesenteric arteries, respectively. These results demonstrate that vascular function is altered at an advanced maternal age and provides further insights into the risks of poor pregnancy outcomes observed in women who delay pregnancy.

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“…The factors responsible for the remodeling of the uterine vasculature during pregnancy, particularly the main uterine artery, are influenced by a combination of local and systemic pregnancy-dependent factors [2,15]. Studies using pseudopregnant mice demonstrated that the conceptus is not involved in the initial remodeling response of the uterine artery [11], but as pregnancy progresses, the fetoplacental unit plays a major role in mediating expansion of the uteroplacental vasculature [16,17].…”

Section: Introductionmentioning

confidence: 98%

Enhanced Uterine Artery Stiffness in Aged Pregnant Relaxin Mutant Mice Is Reversed with Exogenous Relaxin Treatment1

Gooi

Richardson

Jelinic

et al. 2013

Biology of Reproduction

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Pregnancy is associated with a progressive remodeling of the uterine artery. This adaptation is influenced by local and systemic pregnancy-dependent factors. We recently demonstrated that the peptide hormone relaxin mediates uterine artery remodeling in late pregnant rats. The objective of this study in relaxin gene knockout (Rln(-/-)) mice was to test the hypothesis that relaxin deficiency throughout pregnancy disrupts uterine artery remodeling, an effect that is exacerbated by aging and reversed with relaxin treatment. Passive mechanical wall properties and extracellular matrix components were measured using pressure myography, quantitative PCR, and zymography in uterine arteries from pregnant wild-type (Rln(+/+)) and Rln(-/-) mice aged 5 and 8 mo on Days 12.5 and 17.5 pregnancy. In a second study, 8-mo-old Rln(-/-) mice received either placebo or human recombinant relaxin subcutaneously for 5 days from Day 12.5 pregnancy. Relaxin deficiency in pregnancy did not alter uterine artery remodeling in young mice. However, remodeling was impaired in older pregnant Rln(-/-) mice, resulting in significantly stiffer uterine arteries. Uterine arteries of aged Rln(-/-) pregnant mice had increased expression of elastin, whereas several matrix metalloproteinases and cell adhesion molecules were decreased relative to Rln(+/+) mice. Fetal weight was also significantly reduced in Rln(-/-) mice in late pregnancy in both young and old dams, whereas placental weight was unchanged. Arterial stiffness and reduced fetal weight were reversed after relaxin treatment. In conclusion, relaxin deficiency compromises uterine artery remodeling in older pregnant females, increasing the risk of pregnancy complications such as hypertension and intrauterine growth restriction.

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Physiological Remodelling of the Maternal Uterine Circulation during Pregnancy

Cited by 89 publications

References 52 publications

Functional changes in the uterine artery precede the hypertensive phenotype in a transgenic model of hypertensive pregnancy

Functional changes in the uterine artery precede the hypertensive phenotype in a transgenic model of hypertensive pregnancy

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

Enhanced Uterine Artery Stiffness in Aged Pregnant Relaxin Mutant Mice Is Reversed with Exogenous Relaxin Treatment1

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