The role of nitric oxide on matrix metalloproteinase 2 (MMP2) and MMP9 in placenta and fetus from diabetic rats

Pustovrh, María Carolina; Jawerbaum, Alicia; White, Verónica; Capobianco, Evangelina; Higa, Romina; Martínez, Nora; López‐Costa, Juan José; González, Ezequiel

doi:10.1530/rep-06-0267

Cited by 25 publications

(29 citation statements)

References 55 publications

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“…Therefore, we sought to expand on the role of MMPs in pregnancy and delineate the effect of NO inhibition on the expression of MMPs in the late pregnant mUA. MMPs are key proteases involved in remodeling and have been linked to NO signaling (17,33,54). Others (32,45) have established that many MMPs and TIMPs, including MT1-MMP, MMP-2, and TIMP-2, are upregulated during rat pregnancy, especially during the day before parturition.…”

Section: Discussionmentioning

confidence: 99%

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

Hale

Weger

Mandalà

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Hale SA, Weger L, Mandala M, Osol G. Reduced NO signaling during pregnancy attenuates outward uterine artery remodeling by altering MMP expression and collagen and elastin deposition. Am J Physiol Heart Circ Physiol 301: H1266 -H1275, 2011. First published August 19, 2011 doi:10.1152/ajpheart.00519.2011.-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 (Ͼ90%) decreased in the LPLN mUA compared with LP. Collagen and elastin contents were significantly increased in LPLN rats by ϳ10 and 25%, respectively, compared with LP (P Ͻ 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. matrix metalloproteinase; extracellular matrix; hypertension; pregnancy; nitric oxide DURING PREGNANCY, THE UTERINE vasculature undergoes significant expansive remodeling to accommodate the dramatic increase in uteroplacental blood flow that is requisite for normal pregnancy outcome. Studies from our and other laboratories (40,41,44,46,50,61) have established that nitric oxide (NO) is a key molecule involved in vascular remodeling during pregnancy and that expression of endothelial nitric oxide synthase (eNOS) is increased during pregnancy, leading to increased synthesis and release of NO from the endothelium.The importance of NO and NO signaling during pregnancy is underscored by the vascular and reproductive implications evident in mouse knockouts for endothelial NO synthase and in rats treated with the NO inhibitor N G -nitro-L-arginine methyl ester (L-NAME) during pregnancy (50, 64). Tre...

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Section: Discussionmentioning

confidence: 99%

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

Hale

Weger

Mandalà

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…Individual members of the MMP family are regulated independently (Brown et al 1990;Vincenti et al 1998). Pustovrh et al (2007) reported that MMP-9 activity was more susceptible than MMP-2 in placenta and fetus from diabetic rats which treated by nitric oxide. Both ELISA and immunohistochemistry consistently indicated that treatment with low concentrations of MCs (X group) had no obvious effect on MMP-2 expression, but could stimulate the enzyme expression in the mice exposed to the water sampled from more heavily polluted areas (M1, M2 and H group).…”

Section: Discussionmentioning

confidence: 99%

Assessing the toxicity of ingested Taihu Lake water on mice via hepatic histopathology and matrix metalloproteinase expression

et al. 2011

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Water from Taihu Lake (China) is used as a drinking source. The frequency of contamination in Taihu Lake has increased over the past decade and the bloom-forming cyanobacteria are the dominant species during eutrophication. Cyanobacteria can produce various harmful secondary substances including microcystins capable of endangering human health and ecological safety. This study investigated toxicity of ingested Taihu Lake water on mice via hepatic histopathology and matrix metalloproteinase (MMP) expression. Water was sampled from four Taihu Lake locations, Meiliang Bay 2 group (M2), Meiliang Bay 1 group (M1), Lake Center (H) and Xukou Bay (X), along a gradient of decreasing degree of eutrophication. The experimental design consists of five groups of male mice (Mus musculus, ICR): one control and four groups ingesting water from the four sampling sites for 90 days. Compared to control, M1 and M2 mice showed hepatic histopathological changes including swollen, vacuolar degeneration or inflammatory. Immunohistochemical staining demonstrated a higher expression of MMP-2 proteins in M2 group and a lower expression of MMP-9 in M1. Enzyme-linked immunosorbent assay indicated that MMP-9 concentration was significantly reduced from 0.55 to 0.28 ng/g liver weight in M2 (p < 0.05). Real time PCR revealed a down-regulation of MMP-9 mRNA by 2.2 fold in M1 and an up-regulation of MMP-2 mRNA by 1.73 fold in H. Using this mouse model as a gauge of water toxicity, our results revealed that potential health risks induced by Taihu Lake water might arise from the use of this source water by local resident.

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“…Multiple linkages between cellular inputs and outputs further complicate understanding the precise mechanisms involved. For example, VEGF, estrogen, and shear stress all stimulate NO production, and both estrogen and NO regulate matrix metalloproteinase activity and, hence, passive mechanical properties and matrix composition (27, 43, 103). …”

Section: Mechanisms Underlying Gestational Uterine Vascular Remodelingmentioning

confidence: 99%

Maternal Uterine Vascular Remodeling During Pregnancy

2009

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This classification was proposed by Mulvany (86) and is further refined to include consideration of wall mass, which can increase (hypertrophy), decrease (hypotrophy), or remain unchanged (eutrophy). Various patterns of arterial remodeling are shown in FIGURE 1; see legend for additional detail and for consideration of how changes in crosssectional area, a two-dimensional quantity (e.g., m 2 ), relate to changes in wall mass, a three-dimensional quantity (e.g., m 3 ). Uterine Hemodynamics DuringPregnancy; Blood Flow Patterns and the Importance of Placentation Type Uterine vascular anatomyAn overview of comparative uterine vascular anatomy is presented in FIGURE 2, which describes and illustrates the uterine circulation in humans (FIGURE 2A), rodents (FIGURE 2B), and ungulates, such as sheep and pigs. Please see legend for additional detail.Uterine and placental blood flow during pregnancy Early (1953Early ( -1960 human studies by Assali et al (3, 4) and Metcalfe (78) utilizing the diffusion equilibrium principle (most often nitrous oxide, N 2 O) or electromagnetic flow probes placed directly on the uterine artery reported that total uteroplacental blood flow (UPBF) increases from a baseline value of 20-50 ml/min to 450-800 ml/min in singleton pregnancies, with values in excess of 1 l/min measured in twin pregnancy. Subsequent measurements of uterine artery blood flow with 133 Xe (106), placental metabolic clearance rate techniques (29) The clinical relevance of maternal uterine vascular adaptation during pregnancy is underscored by the fact that its aberrance is associated with several common gestational pathologies, including intrauterine growth restriction, gestational diabetes, and preeclampsia.In addition to the changes in vessel structure, uterine vascular reactivity is also altered during pregnancy, with the general pattern being one of reduced tone and enhanced vasodilation/blunted vasoconstriction (52,72,111,112,118). Space limitations preclude indepth consideration of the ionic and enzymatic mechanisms that underlie reactivity, but it is worth noting that, in vivo, uterine vascular resistance (and, therefore, blood flow) is ultimately determined by the combination of vessel size and reactivity.We also avoid examining the complex angiogenic mechanisms associated with implantation and placentation, other than to consider how hemochorial vs. epitheliochorial placentation influences uterine hemodynamics and vascular remodeling. Although the remodeling of spiral arteries by fetal trophoblast is considered, the main focus of this review is on upstream maternal uterine arteries and veins, since the processes involved in their remodeling have not been reviewed to date. Readers interested in endovascular trophoblast invasion and mechanisms underlying spiral artery remodeling are referred to several reviews on this subject (9, 31, 71, 101). Nomenclature Used to Describe Vascular RemodelingCircumferential remodeling is normally termed inward or outward to denote narrowing vs. widening of the vessel lumen. The ...

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The role of nitric oxide on matrix metalloproteinase 2 (MMP2) and MMP9 in placenta and fetus from diabetic rats

Cited by 25 publications

References 55 publications

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

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

Assessing the toxicity of ingested Taihu Lake water on mice via hepatic histopathology and matrix metalloproteinase expression

Maternal Uterine Vascular Remodeling During Pregnancy

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