Plasticity of the Maternal Vasculature During Pregnancy.

Maternal cardiovascular changes during pregnancy include an expansion of plasma volume, increased cardiac output, decreased peripheral resistance, and increased uteroplacental blood flow. These adaptations facilitate the progressive increase in uteroplacental perfusion that is required for normal fetal growth and development, prevent the development of hypertension, and provide a reserve of blood in anticipation of the significant blood loss associated with parturition. Each woman's genotype and phenotype determine her ability to adapt in response to molecular signals that emanate from the fetoplacental unit. Here, we provide an overview of the major hemodynamic and cardiac changes and then consider regional changes in the splanchnic, renal, cerebral, and uterine circulations in terms of endothelial and vascular smooth muscle cell plasticity. Although consideration of gestational disease is beyond the scope of this review, aberrant signaling and/or maternal responsiveness contribute to the etiology of several common gestational diseases such as preeclampsia, intrauterine growth restriction, and gestational diabetes.

Enhanced Vascular Smooth Muscle Calcium Sensitivity and Loss of Endothelial Vasodilator Influence Contribute to Myogenic Tone Development in Rat Radial Uterine Arteries during Gestation.

Uterine artery myogenic tone (MT) develops during pregnancy in hemochorial placentates such as rats and humans. The physiological reason for its appearance is not clear, and we reasoned that it may be a late pregnancy (LP) event in preparation for controlling hemorrhage during parturition. We also hypothesized that gestational increases in RhoA-induced vascular smooth muscle (VSM) calcium sensitivity are contributory and occur under the tonic influence of nitric oxide (NO). Second-order pre-placental radial arteries from early-pregnant (day 12, n = 5), mid-pregnant (day 16, n = 5) and LP (day 20, n = 20) rats were used in combination with arteriography, VSM calcium measurements, pharmacological RHO/Rho-associated protein kinase (ROCK) and nitric oxide synthase (NOS) inhibition, and Western blotting. A subgroup of LP animals (LP + LN; n = 5) treated with L-NAME from gestational days 10 to 20 were used to determine the effects of NOS inhibition on MT and RhoA expression. MT was evident throughout pregnancy, but its expression in pressurized vessels was masked by endothelial NO-induced vasodilation during early gestation. RhoA protein expression was upregulated in LP and attenuated by in vivo NOS inhibition (as was MT). In vitro RHO/ROCK inhibition decreased MT in a concentration-dependent manner without reducing VSM calcium. In summary, pressure-dependent uterine artery tone increases with gestational age due to a combination of RhoA-mediated increases in VSM calcium sensitivity and a loss of endothelial NO influence.

Venoarterial communication mediates arterial wall shear stress-induced maternal uterine vascular remodeling during pregnancy.

Although expansive remodeling of the maternal uterine circulation during pregnancy is essential for maintaining uteroplacental perfusion and normal fetal growth, the underlying physiological mechanisms are not well understood. Using a rat model, surgical approaches were used to alter uterine hemodynamics and wall shear stress (WSS) to evaluate the effects of WSS and venoarterial communication (e.g., transfer of placentally derived growth signals from postplacental veins to preplacental arteries) on gestational uterine vascular remodeling. Changes in WSS secondary to ligation of the cervical but not the ovarian end of the main uterine artery and vein provoked significant expansive remodeling at the opposite end of both vessels, but only in pregnant animals. The ≈50% increase in lumen diameter (relative to the contralateral horn) was associated with an upregulation of total endothelial nitric oxide (NO) synthase expression and was abolished by in vivo NO synthase inhibition with N-nitro-l-arginine methyl ester. Complete removal of a venous segment adjacent to the uterine artery to eliminate local venous influences significantly attenuated the WSS-induced remodeling by about one-half ( P < 0.05). These findings indicate that, during pregnancy, 1) increased WSS stimulates uterine artery growth via NO signaling and 2) the presence of an adjacent vein is required for arterial remodeling to fully occur. NEW & NOTEWORTHY This study provides the first in vivo evidence for the importance of venous influences on arterial growth within the uteroplacental circulation.

The Piezo1 cation channel mediates uterine artery shear stress mechanotransduction and vasodilation during rat pregnancy.

During mammalian pregnancy, the uterine circulation must undergo substantial vasodilation and growth to maintain sufficient uteroplacental perfusion. Although we and others have shown that nitric oxide (NO) is a key mediator of these processes, the mechanisms that augment uterine artery NO signaling during gestation have not been identified. We hypothesized that Piezo1, a recently discovered cation channel, may be involved in the process of shear stress mechanotransduction, as other studies have shown that it is both mechanosensitive and linked to NO production. Surprisingly, there are no studies on Piezo1 in the uterine circulation. Our aims in the present study were to determine whether this novel channel is 1) present in uterine arteries, 2) regulated by gestation, 3) functionally relevant (able to elicit rises in intracellular Ca2+ concentration and vasodilation), and 4) linked to NO. Immunohistochemistry confirmed that Piezo1 is present in uterine arteries, primarily but not exclusively in endothelial cells. Western blot analysis showed that its protein expression was elevated during gestation. In pressurized main uterine arteries, pharmacological activation of Piezo1 by Yoda1 produced near maximal vasodilation and was associated with significant increases in intracellular Ca2+ concentration in endothelial cell sheets. Shear stress induced by intraluminal flow produced reversible vasodilations that were inhibited >50% by GsMTx-4, a Piezo1 inhibitor, and by Nω-nitro-l-arginine methyl ester/ Nω-nitro-l-arginine, inhibitors of NO synthase. These findings are the first to implicate a functional role for Piezo1 in the uterine circulation as a mechanosensor of endothelial shear stress. Moreover, our data demonstrate that Piezo1 activation leads to vasodilation via NO and indicate that its molecular expression is upregulated during pregnancy. NEW & NOTEWORTHY This is the first study to highlight Piezo1 in the uterine circulation. As a potentially important endothelial mechanosensor of shear stress, Piezo1 may be linked to mechanisms that support increased uteroplacental perfusion during pregnancy. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/piezo1-mechanotransduction-in-the-uterine-circulation/ .

Pregnancy-Induced Physiologic Adaptation of the Abdominal Aorta Is Associated with Changes in Gene Expression and Genomic Methylation.

BACKGROUND/AIMS: Ten-eleven translocation 2 (Tet2), a DNA demethylase enzyme, has been identified as a master epigenetic regulator of vascular smooth muscle cell plasticity. We hypothesized that pregnancy will induce significant adaptive changes in aortic biomechanics that correlate with the Tet family gene expression. METHODS: Abdominal aortas from pregnant and nonpregnant mice were dissected and cannulated. Intraluminal pressure was adjusted using a pressure-servo system while using a video dimension analyzer to measure the lumen diameter. Quantitative polymerase chain reaction and immunoblot was used to analyze the expression of Tet genes. Global genomic methylation was assessed with the luminometric methylation assay. RESULTS: Compared to the nonpregnant (NP, 706 ± 8 µm) control group, the aortic luminal diameter was significantly increased in both E18.5 (836 ± 14 µm) and PP30 (889 ± 16 µm) mice. Distensibility was reduced in E18.5 (90 ± 4%) mice and returned to NP values (108 ± 2%) in PP30 (108 ± 3%) mice. Tet2 transcription decreased at the beginning of pregnancy and subsequently increased in late gestation, inversely corresponding to changes in global methylation. CONCLUSION: Physiologic changes in the aorta were accompanied by changes in gene expression and genomic methylation, suggesting an epigenetic component to maternal vascular remodeling during pregnancy.

Altered Endothelial Nitric Oxide Signaling as a Paradigm for Maternal Vascular Maladaptation in Preeclampsia.

PURPOSE OF REVIEW: The goal of this review is to present the newest insights into what we view as a central failure of cardiovascular adaptation in preeclampsia (PE) by focusing on one clinically significant manifestation of maternal endothelial dysfunction: nitric oxide signaling. The etiology, symptoms, and current theories of the PE syndrome are described first, followed by a review of the available evidence, and underlying causes of reduced endothelial nitric oxide (NO) signaling in PE. RECENT FINDINGS: PE maladaptations include, but are not limited to, altered physiological stimulatory inputs (e.g., estrogen; VEGF/PlGF; shear stress) and substrates (L-Arg; ADMA), augmented placental secretion of anti-angiogenic and inflammatory factors such as sFlt-1 and Eng, changes in eNOS (polymorphisms, expression), and reduced bioavailability of NO secondary to oxidative stress. PE is a complex obstetrical syndrome that is associated with maternal vascular dysfunction. Diminished peripheral endothelial vasodilator influence in general, and of NO signaling specifically, are key in driving disease progression and severity.

Placental Protein 13 Administration to Pregnant Rats Lowers Blood Pressure and Augments Fetal Growth and Venous Remodeling.

Reduced first-trimester concentrations of placental protein 13 (PP13) are associated with subsequent development of preeclampsia, a major pregnancy disorder. We previously showed that PP13 has a vasodilatory effect, reduces blood pressure and augments expansive remodeling of the uteroplacental vasculature in pregnant rats. In this study, slow-release osmotic pumps were implanted in gravid rats (on day 8) to provide 1 week of PP13 supplementation. Treatment was associated with a reversible blood pressure reduction that returned to normal on day 15. In addition, PP13 caused venous expansion that is larger in the venous branches closer to the placenta. Then, it increased placental and pup weights. Similar administration of a truncated PP13 variant (DelT221) that is unable to bind carbohydrates (a rare spontaneous mutation associated with a high frequency of severe early preeclampsia among Blacks in South Africa) produced a hypotensive effect similar to the full-length molecule, but without venous remodeling and increased placental and pup weights. These results indicate the importance of PP13 carbohydrate binding for inducing vascular remodeling and improving reproductive outcome. Future studies are needed to determine whether beneficial effects would be evident in animal models of preeclampsia or in women predisposed to the development of preeclampsia.

Maternal uterine vascular remodeling during pregnancy.

Remodeling of the maternal uterine vasculature during pregnancy is a unique cardiovascular process that occurs in the adult and results in significant structural and functional changes in large and small arteries and veins, and in the creation of the placenta--a new fetomaternal vascular organ. This expansive, hypertrophic process results in increases in both lumen circumference and length, and is effected through a combination of tissue and cellular hypertrophy, endothelial and vascular smooth muscle hyperplasia, and matrix remodeling. This review summarizes what is currently known about the time course and extent of the remodeling process, and how local vs. systemic factors influence its genesis. The main focus is on upstream maternal vessels rather than spiral artery changes, although the latter are considered from the overall hemodynamic perspective. We also consider some of the underlying mechanisms and provide a hypothetical scenario that integrates our current knowledge. Abrogation of this adaptive vascular process is associated with several human gestational pathologies such as preeclampsia and intrauterine growth restriction (IUGR), which not only raise the risk of infant mortality and morbidity but are also a significant source of maternal mortality and susceptibility to cardiovascular and other diseases for both mother and neonate later in life.

Preeclampsia and maternal cardiovascular disease: consequence or predisposition?

Formerly preeclamptic women stand a higher chance of developing cardiovascular disease (CVD) later in life and may experience a shortened life span. This review updates the pathophysiology and definition of this complex disease and highlights the protective role of pregnancy by considering the relationship between pregnancy interval and likelihood of disease recurrence. The evidence for persistent maternal cardiovascular impairment following preeclampsia (PE) is considered, e.g. postpartum changes in CVD occurrence, blood pressure elevation and changes in the renin-angiotensin-aldosterone system). Since maternal endothelial dysfunction is a hallmark of PE, we summarize the evidence for reduced flow-mediated dilation in women with previous PE, and consider the utility and shortcomings of this clinical measure. In addition to viewing postpartum changes as a consequence of this disease, we consider the alternative view that PE might be the manifestation of a maternal phenotype that already has some predisposition to or is in the earlier stages of CVD; in this case, some of the postpartum residual deficits (or their antecedents) may have already been present prior to pregnancy. Finally, we consider the use of novel biomarkers for predicting or detecting PE prior to the appearance of clinical symptoms.

Effects of placental protein 13 on the cardiovascular system in gravid and non-gravid rodents.

OBJECTIVES: Here, we performed a pathophysiological examination of the vascular function of rodent in the presence of placental protein 13 (PP13) and its implication to regulate the development of preeclampsia. METHODS: Single i.v. injection and prolonged in vivo exposure to PP13 via osmotic pumps were performed in gravid and non-gravid rats to examine the influence of PP13 on blood pressure and heart rate in animals. The effect of PP13 was also examined in isolated uterine and mesenteric arteries, along with the examination of placental blood supply. RESULTS: Human PP13 has a major impact on the maternal cardiovascular system of rodents by reducing blood pressure, either at single or prolonged exposure, and causing significant vasodilatation in isolated arteries. Prolonged exposure was followed by increased elaboration and angiogenesis of the uteroplacental arteries supplying the placenta. CONCLUSION: This is the first study describing effects of PP13 on vasodilatation and uterine artery remodeling. The results imply that PP13 may have a physiological role in improving uteroplacental blood flow. The findings of this study make it tempting to speculate that keeping PP13 levels within a certain 'therapeutic window' during pregnancy may facilitate proper adaptation of the maternal vasculature to pregnancy.

Influence of constriction, wall tension, smooth muscle activation and cellular deformation on rat resistance artery vasodilator reactivity.

This study investigated how vasoconstriction (tone), wall tension, smooth muscle activation, and vascular wall deformation influence resistance artery vasodilator reactivity. Resistance arteries, from two different regional circulations (splanchnic, uterine) and from pregnant and non-pregnant rats, were cannulated and pressurized, or mounted on a wire myograph under isometric conditions prior to being exposed to both endothelium-dependent (acetylcholine, ACh) and -independent (sodium nitroprusside, SNP) vasodilator agonists. A consistent pattern of reduced vasodilator sensitivity was noted as a function of extent of preconstriction for both agonists noted in pressurized arteries. A similar pattern regarding activation was noted in wire-mounted arteries in response to SNP but not ACh. Wall tension proved to be a major determinant of vascular smooth muscle vasodilator reactivity and its normalization reversed this pattern, as more constricted vessels were more sensitive to ACh relaxation without any change in SNP sensitivity, suggesting that endothelial deformation secondary to vasoconstriction augments its vasodilator output. To our knowledge, this is the first study to dissect out the complex interplay between biophysical forces impinging on VSM (pressure, wall tension), the ambient level of tone (vasoconstriction, smooth muscle cell activation), and consequences of cellular (particularly endothelial) deformation secondary to constriction in determining resistance artery vasodilatory reactivity.

Hemodynamic, vascular, and reproductive impact of FMS-like tyrosine kinase 1 (FLT1) blockade on the uteroplacental circulation during normal mouse pregnancy.

To investigate the role of FMS-like tyrosine kinase 1 (FLT1, also known as VEGFR1) signaling during pregnancy, mice were injected with anti-FLT1 neutralizing antibody (Ab) beginning on Gestational Day 8 or 12 and every other day thereafter until Day 18; vehicle-only injected mice served as controls. Uterine artery blood flow was measured with ultrasound on Days 13 and 18, and morphometric measurements of the uterine arcade were carried out on Day 19 to provide a measure of gestational vascular remodeling; reproductive performance was evaluated by determining litter size, resorption rates, and pup and placental weights. Ab injections beginning on Day 8 or Day 12 resulted in significant reductions of uterine artery peak systolic and diastolic flows at Days 13 and 18. In addition, normal reproductive function was compromised, as evidenced by a significant reduction in average number of viable pups along with enhanced resorption rates. Reproductive performance was also significantly compromised in this group, although less severely. There was no evidence of a reduction in main uterine artery diameters, though arterial distensibility was reduced, and the diameter of the main uterine vein was significantly smaller in the Ab-injected mice. Significant reductions in main uterine artery and segmental artery length were also noted. Placental and pup weights were similar in all the groups. FLT1 inhibition during murine pregnancy impaired blood flow to the fetal-placental unit, compromised several indices of vascular remodeling, reduced fecundity, and increased fetal reabsorptions. The effects of FLT1 inhibition are most pronounced when targeted during early pregnancy.

Endothelial-derived hyperpolarization factor (EDHF) contributes to PlGF-induced dilation of mesenteric resistance arteries from pregnant rats.

The aim of this study was to investigate the cellular mechanism involved in the potent vasodilatory action of PlGF on mesenteric resistance arteries from pregnant rats. PlGF (3 nM) induced a vasodilation of 64 ± 3.8% that was completely abolished by endothelial denudation. Significant dilation (28 ± 4.0%) remained, however, in the presence of nitric oxide synthase and cyclooxygenase inhibition, and was associated with significant reductions in vascular smooth muscle cell calcium. Absence of dilation in potassium-depolarizing solution (30 mM) confirmed its dependence on endothelial-derived hyperpolarization factor. Subsequent studies established that vasodilation was abolished by pharmacologic inhibition of SK(Ca) (apamin) and BK(Ca) (iberiotoxin) but not IK(Ca) (tram-34) potassium channels. In summary, PlGF acts through the release of a combination of endothelium-derived relaxation factors. Based on the results of potassium channel blockade, we suggest that it induces endothelial hyperpolarization via SK(Ca) channel activation; this, in turn, leads to the release of a diffusible mediator that activates vascular smooth muscle BK(Ca) channels, hyperpolarization and vasodilation. This is the first study to identify the mechanism for PlGF/VEGFR-1 resistance artery dilation in the pregnant state, whose attenuation likely contributes to the systemic hypertension characteristic of pre- eclampsia.

Uterine distension differentially affects remodelling and distensibility of the uterine vasculature in non-pregnant rats.

During pregnancy the mammalian uterine circulation undergoes significant expansive remodelling necessary for normal pregnancy outcome. The underlying mechanisms are poorly defined. The goal of this study was to test the hypothesis that myometrial stretch actively stimulates uterine vascular remodelling by developing a new surgical approach to induce unilateral uterine distension in non-pregnant rats. Three weeks after surgery, which consisted of an infusion of medical-grade silicone into the uterine lumen, main and mesometrial uterine artery and vein length, diameter and distensibility were recorded. Radial artery diameter, distensibility and vascular smooth muscle mitotic rate (Ki67 staining) were also measured. Unilateral uterine distension resulted in significant increases in the length of main uterine artery and vein and mesometrial segments but had no effect on vessel diameter or distensibility. In contrast, there were significant increases in the diameter of the radial arteries associated with the distended uterus. These changes were accompanied by reduced arterial distensibility and increased vascular muscle hyperplasia. In summary, this is the first report to show that myometrial stretch is a sufficient stimulus to induce significant remodelling of uterine vessels in non-pregnant rats. Moreover, the results indicate differential regulation of these growth processes as a function of vessel size and type.

Reduced NO signaling during pregnancy attenuates outward uterine artery remodeling by altering MMP expression and collagen and elastin deposition.

Recent findings indicate that endothelial nitric oxide (NO) plays a key role in uterine artery outward circumferential remodeling during pregnancy. Although the underlying mechanisms are not known, they likely involve matrix metalloproteinases (MMPs). The goal of this study was to examine the linkage among NO inhibition, expansive remodeling, and MMP expression within the uterine vascular wall. Adult female rats were treated with N(G)-nitro-L-arginine methyl ester [L-NAME (LPLN)] beginning on day 10 of pregnancy and until death at day 20 and compared with age-matched controls [late pregnant (LP)]. Mean arterial pressure of LPLN rats was significantly higher than controls. LPLN fetal and placental weights were significantly reduced compared with controls. Main uterine arteries (mUA) were collected to determine dimensional properties (lumen area and wall thickness), collagen and elastin content, and levels of endothelial nitric oxide synthase (eNOS) and MMP expression. Circumferential remodeling was attenuated, as evidenced by significantly smaller lumen diameters. eNOS RNA and protein were significantly (>90%) decreased in the LPLN mUA compared with LP. Collagen and elastin contents were significantly increased in LPLN rats by ∼10 and 25%, respectively, compared with LP (P < 0.05). Both MMP-2 and tissue inhibitors of metalloproteinase-2 as assessed by immunofluorescence were lower in the endothelium (reduction of 60%) and adventitia (reduction of 50%) of LPLN compared with LP mUA. Membrane bound MMP-1 (MT1-MMP) as assessed by immunoblot was significantly decreased in LPLN. These data suggest a novel contribution of MMPs to gestational uterine vascular remodeling and substantiate the linkage between NO signaling and gestational remodeling of the uterine circulation via altered MMP, TIMP-2, and MT1-MMP expression and activity.

Normalization of wall shear stress as a physiological mechanism for regulating maternal uterine artery expansive remodeling during pregnancy.

Outward remodeling of the maternal uterine circulation during pregnancy is essential for normal uteroplacental perfusion and pregnancy outcome. The physiological mechanism by which this process is regulated is unknown; we hypothesized that it involved the normalization of wall shear stress (WSS). Pregnant Sprague-Dawley rats underwent unilateral ligation of the main uterine artery and vein at the cervical end of the uterus on gestational day 10, thus restricting inflow/outflow of blood into that uterine horn to a single point at the ovarian end; the contralateral sham-operated side provided an internal control. This procedure alters uterine hemodynamics by increasing WSS, since the entire uterine horn is supplied by one rather than two vessels. Arterial diameter and blood flow velocity values were measured by intravital ultrasonographic pulse-wave Doppler on gestational day 20 and used to calculate WSS. Although both ovarian artery lumen diameter and blood velocity increased, WSS was similar in both horns. These data support the concept that increased WSS secondary to hemochorial placentation is the primary physiological stimulus for uterine vascular remodeling and that its normalization may be the primary mechanism that regulates the extent of arterial circumferential growth required to maintain placental perfusion. We further hypothesize that shallow spiral artery invasion, such as occurs in preeclampsia, limits the increase in upstream shear stress and results in attenuated remodeling and placental under-perfusion.

Effects of pregnancy, hypertension and nitric oxide inhibition on rat uterine artery myogenic reactivity.

BACKGROUND/AIMS: The purpose of this study was to examine the effects of hypertension and nitric oxide (NO) inhibition on myogenic tone in uterine arteries during pregnancy. METHODS: Premyometrial radial uterine arteries from nonpregnant and late pregnant Sprague-Dawley rats were evaluated for myogenic reactivity from the following groups: control, hypertensive/NO-inhibited (L-NAME treatment) and normotensive/NO-inhibited (L-NAME plus hydralazine). RESULTS: In both nonpregnant and pregnant animals, L-NAME treatment significantly elevated blood pressures, while the addition of hydralazine made the animals normotensive. In nonpregnant animals, little myogenic tone was seen in controls; tone increased significantly in the L-NAME group, and was attenuated in those treated with L-NAME plus hydralazine. In pregnant animals, controls developed significant tone; this was reduced in the L-NAME group, and returned to control levels in the L-NAME plus hydralazine group. CONCLUSIONS: Dimensional measurements showed that arteries from the pregnant hypertensive group did not undergo expansive remodeling, suggesting that tone development is related to phenotypic alterations in vascular smooth muscle and/or altered physical forces secondary to adaptive changes in arterial diameter. These differences implicate pregnancy-specific pathways in the development and inhibition of myogenic tone, and point to potentially opposing roles of NO and hypertension.

Correction to: Postpartum Persistence of Maternal Uterine Vascular Gestational Adaptation in Rodents.

A reference that may be of interest to readers was inadvertently omitted.

Postpartum Persistence of Maternal Uterine Vascular Gestational Adaptation in Rodents.

Although pregnancy has long-lasting consequences for maternal vascular health, little is known about vascular changes postpartum (PP). Focusing on the uterine circulation, which undergoes unique structural and functional adaptation during gestation, we hypothesized that most pregnancy-induced changes would return to baseline PP, with minimal hysteresis. Large (main; MUA) and small (segmental; SUA) uterine arteries from adult Sprague Dawley rats (n = 42) were evaluated 1 and 4 weeks PP (1PP, 4PP) and compared with those of late-pregnant (LP, day 21) and age-matched non-pregnant (NP) animals. Some comparisons were extended to mesenteric arteries to evaluate differences between reproductive and systemic vessels. Pregnancy-induced axial elongation regressed > 80% 1PP in MUAs and SUAs, although some minimal hysteresis remained 4PP. Circumferential growth was slower to regress, with no reductions in lumen diameter or media thickness 1PP; values returned to (MUA) or approached (SUA) NP values by 4PP. Changes in vascular smooth muscle cell cross-sectional area-a measure of hypertrophy-paralleled those in lumen diameter. Mesenteric and uterine artery compliance diverged during gestation, and continued to do so PP. Decreased MUA compliance 4PP was supported by an increased collagen:elastin ratio. Adrenergic sensitivity increased in uterine, and decreased in mesenteric arteries during pregnancy, and returned to NP values 4PP in both types of vessels. MUA α-1 adrenoceptor expression tracked along with sensitivity. Thus, postpartum adaptation varies by both parameter and vessel type. While many parameters regressed postpartum, alterations in compliance did not, suggesting that matrix changes may have long-term consequences for maternal vascular function and health.

Inhibition of nitric oxide synthases abrogates pregnancy-induced uterine vascular expansive remodeling.

BACKGROUND/AIMS: It was the aim of this study to test the hypothesis that hypertension and/or inhibition of nitric oxide (NO) synthases alters uterine vascular remodeling during pregnancy. METHODS: Using a model of hypertension (NO synthase inhibition with L-NAME) in nonpregnant and pregnant rats, comparisons were made with age-matched controls, as well as with animals receiving hydralazine along with L-NAME to maintain normotension in the presence of NO synthase inhibition. Circumferential and axial remodeling of large (main uterine, MUA) and small (premyometrial radial) arteries were quantified and compared. RESULTS: L-NAME treatment prevented expansive circumferential remodeling of the MUA; cotreatment with hydralazine was without effect. Circumferential remodeling of smaller premyometrial radial arteries was also significantly attenuated in hypertensive pregnant animals, while premyometrial radial arteries from rats receiving hydralazine with L-NAME were of intermediate diameter. Neither hypertension nor NO synthase inhibition had any effect on the substantial (200-300%) axial growth of MUA or premyometrial radial arteries. CONCLUSION: NO plays a major role in facilitating pregnancy-induced expansive remodeling in the uterine circulation, particularly in larger arteries. Some beneficial effects of hydralazine on expansive circumferential remodeling were noted in smaller radial vessels, and these may be linked to its prevention of systemic hypertension and/or to local effects on the arterial wall. Neither NO synthase inhibition nor hypertension had any effect on arterial longitudinal growth.