| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
RESEARCH |
1 Laboratory of Reproduction and Metabolism, Center for Pharmacological and Botanical Studies, CEFyBO-CONICET and 2 Institute of Cellular Biology and Neurosciences ‘Prof. E De Robertis’, School of Medicine, University of Buenos Aires, Paraguay 2155 (C1121ABG), Buenos Aires, Argentina
Correspondence should be addressed to M C Pustovrh; Email: carolinapustovrh{at}yahoo.com.ar
 |
Abstract |
|---|
 Top Abstract IntroductionResultsDiscussionMaterials and MethodsAcknowledgementsReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionResultsDiscussionMaterials and MethodsAcknowledgementsReferences |
|---|
On the other hand, nitric oxide (NO) is a gaseous messenger produced from L-arginine through a reaction catalyzed by the three isoforms of NO synthases (NOS): calmodulin- and Ca++2 -dependent endothelial (eNOS) and neuronal synthases (nNOS), and calmodulin- and Ca++ 2 -independent NOS (iNOS). NO is implicated in reproductive events such as ovulation, decidualization, and implantation (Jablonka-Shariff & Olson 1997, Novaro et al. 1997, Zhang et al. 2005). During late pregnancy, NO is involved in the maintenance of a low vascular resistance, attenuating the action of vasoconstrictors (Baylis et al. 1998). Due to its unpaired e– , NO is able to react with amino acid residues or thiol groups in protein molecules, leading to enzyme activation or inhibition. Regarding matrix metalloproteinases (MMP2) and (MMP9), NO is capable of modulating its activation through the disruption of the union between an atom of Zn and a residue of cysteine located in the catalytic site of the proenzymes (Gu et al. 2002, Novaro et al. 2002, Pustovrh et al. 2002). In the diabetic pathology, NO imbalance is involved in the development of cardiovascular impairment (Mungrue et al. 2002), pancreatic damage (Gonzalez et al. 1999, 2001), nephropathy (Levine 2006), and retinopathy (Park et al. 2006). Our previous reports have shown that NO is overproduced in placental tissue and embryos from diabetic experimental models (Jawerbaum et al. 2005, Pustovrh et al. 2005). This increase is likely to be associated with both placental dysfunction and diabetic embryopathy (Jawerbaum & Gonzalez 2005, Jawerbaum & González 2006). On the other hand, hyperglycemia also induces an excessive production of uterine, placental, and fetal MMPs (Pustovrh et al. 2000, 2002, 2005).
Alterations in MMPs expression may be the result of NO overexpression, since NO is able to increase MMPs expression and to activate their zymogens in several tissues and cell types (Novaro et al. 2001, Pustovrh et al. 2002, Gursoy-Ozdemir et al. 2004, Yu et al. 2005).
In the present study, we hypothesize that NO may regulate MMPs activity in the feto-placental unit. Moreover, we propose that the diabetic maternal environment may alter the regulatory homeostasis exerted by NO on tissue remodeling at midgestation. In order to verify our hypothesis, we evaluated (i) the expression and localization of fetal and placental NADPH-diaphorase (which reflects the distribution and activity of NOS), (ii) the protein expression of iNOS and eNOS, and (iii) the influence of both NO donors and NOS inhibitors on MMP2 and MMP9 activities in fetuses and placentas from control and diabetic rats.
|
Results |
|---|
|
TopAbstractIntroductionResultsDiscussionMaterials and MethodsAcknowledgementsReferences |
|---|
). The optical density analysis showed a higher NADPH-diaphorase activity in the diabetic placenta (0.133 ± 0.009; mean ± S.E.M.) when compared with controls (0.0790 ± 0.006; P < 0.001); this activity was localized in the same zones as those of controls (Fig. 1B).
|
). In the diabetic group, the NADPH-diaphorase detection showed a significant increase in the enzyme activity when compared with controls in both the thoracic region (control: 0.073 ± 0.04, diabetic: 0.165 ± 0.007; P < 0.001) and the cardiac region of diabetic fetuses (control: 0.079 ± 0.005, diabetic: 0.207 ± 0.006; P < 0.001) This increase was higher in the cardiac than in the thoracic region of diabetic fetuses (P < 0.001; Fig. 2C and D).
|
and 4).
|
|
).
When MMPs were analyzed in the fetal placental side from both controls and diabetic rats, we found that neither MMP2 nor MMP9 activities were affected by NP. Differently, the presence of L-NAME significantly decreased MMP9 activity (P < 0.05) in both experimental groups. On the other hand, MMP2 activity, which was absent in the fetal side of the control placenta, was not modified by L-NAME in the diabetic group (Fig. 4).
Both pro-MMP2 and pro-MMP9 have also been detected and quantified in both maternal and fetal placental sides. As previously stated (Pustovrh et al. 2005), these proenzymes were increased in diabetic tissues when related to controls (P < 0.05). However, pro-MMP2 and pro-MMP9 levels were not modified in the presence of either NP or L-NAME, both in the maternal and fetal placental sides obtained from both control and diabetic rats (Figs 3 and 4).
On the other hand, MMP9 activity could not be detected in the fetuses by zymography at this developmental stage. MMP2 activity was enhanced in diabetic fetuses when compared with controls, and further increased in the presence of NP, in fetuses from both control (P < 0.01) and diabetic (P < 0.05) animals when compared with fetuses incubated without additions. Moreover, blockade of NOS activity promoted a decrease of MMP2 activity in fetuses from control (P < 0.01) and diabetic (P < 0.01) rats when compared with their respective basal activities (Fig. 5).
|
).
Concentrations of inducible and endothelial NOS in placenta and fetus
The evaluation of NO synthase isoenzymes (eNOS and iNOS) by Western blot showed that there were no changes in the concentrations of these NOS isoenzymes -in the placenta from diabetic animals when compared with controls (Fig. 6). Similar concentrations of eNOS and iNOS were also found when the fetuses from control and diabetic animals were evaluated (Fig. 7).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionResultsDiscussionMaterials and MethodsAcknowledgementsReferences |
|---|
In the present work, we found that NADPH-diaphorase was increased in both the maternal and fetal sides of the diabetic placenta when compared with control rats. As the NADPH-diaphorase activity detected by the employed methodology is coupled with NOS, NADPH-diaphorase activity can be used as a marker for NOS activity (Gabbott & Bacon 1993, Loesch et al.1993).
This NOS activity increase may be a main factor in the induction of placental nitrosative stress due to maternal diabetes, and may be related to the induction of other reactive nitrogen species. Indeed, our previous findings (Pustovrh et al. 2005) showed a nitrotyrosine localization pattern similar to that of MMP2 and MMP9 in the diabetic placenta at midgestation that may be involved in the etiology of morphological disarrangements in the diabetic placenta.
Despite the clear increase in NOS activity in both fetuses and placenta from diabetic rats, we did not find changes in the levels of either iNOS or eNOS, suggesting that post-transcriptional mechanisms are involved in diabetes-induced upregulation of NOS in the feto-placental unit. Indeed, in addition to the regulation of NOS isoforms at the transcriptional level, cumulative evidence show different mechanisms of post-translational regulation of NOS isoforms in several cell types. These mechanisms seem to act mainly through the phosphorylation of tyrosine and depend on the activation of MAPK or Akt signaling systems (Rolle et al. 2002, Namkoong et al. 2005, Hausel et al. 2006)
During invasive events, MMPs are frequently expressed by both the invasive cells and the adjacent stroma. Particularly in implantation, MMPs are secreted by the invasive trophoblasts, as well as by the decidual stromal cells (Salamonsen 1999). MMPs are associated with the erosion of maternal structures during embryo implantation, including trophoblastic invasion of maternal vessels, neoangiogenesis, and the development of the labyrinth layer (Blankenship & King 1994, Solberg et al. 2003, Walter & Schonkypl 2006). In experimental models of diabetes, we have previously reported an increase in uterine MMPs activities during the implantation period (Pustovrh et al. 2002). We have also found that MMPs are highly activated in the placenta from rats at midgestation and from pregestational diabetic women at term (Pustovrh et al. 2000, 2005). Our evidence suggests that an early disturbance of placental development due to maternal hyperglycemia may be persistent through out the whole placental life. Moreover, these alterations are likely to be related to an abnormal proliferation and growth of peripheral villi and with the increased vascularization and functional insufficiency of the placenta from diabetic women. Additional studies are necessary to determine the link between an abnormal remodeling and the structural and functional alterations found in the diabetic placenta.
Previous works have demonstrated that NO is able to increase MMP2 and MMP9 activities in the uterus from both control and diabetic rats (Novaro et al. 2002, Pustovrh et al. 2002) and in term human placenta and trophoblast cells in culture (Pustovrh et al. 2000, Novaro et al. 2001). Several pathways have been proposed for the mechanisms of action of NO on MMPs expression and activity. Interestingly, NO can down-regulate the expression of MMPs genes either through the activation of both the nuclear factor-
B (NF-B) and the activated protein-1 or by affecting the stability of their mRNA (Eberhardt et al. 2000, 2002, Akool el et al. 2003). At the post-translational level, NO is able to modulate the activity of the pro-MMPs through the disruption of the union between an atom of Zn and a residue of cysteine located in the catalytic site of the proenzymes (Gu et al. 2002). In this work, we found that NO did not induce changes in the pro-MMPs levels in the feto-placental unit, but clearly upregulates the activity of these enzymes. Indeed, in the maternal placental side, NO modulates MMP2 and MMP9 activities in the control group and MMP9 activity in diabetic animals. However, in the fetal placental side, NO did not influence the MMP2 activity, and, although L-NAME inhibited MMP9 activity in both experimental groups, NP was not able to alter this parameter. These findings suggest that the fetal placental tissue, originated from extraembryonic cells, is more resistant to NO than the placental tissue from maternal origin, a characteristic that may imply a protection from a putative damage by an abnormal maternal environment against the fetus.
On the other hand, NO plays an important role in the post-implantation embryo development. Different works have shown the influence of NO on neural development and differentiation (Peunova & Enikolopov 1995, Wu et al. 2000), lung branching morphogenesis and angiogenesis (Galambos et al. 2002, Young et al. 2002), and cardiomyogenesis and myocardial angiogenesis (Bloch et al. 1999, Zhao et al. 2002). Specifically, eNOS-deficient mice show cardiac valves and ventricular septal defects (Feng et al. 2002, Lee et al. 2000). Furthermore, murine embryonic heart has been found to express iNOS and eNOS in the tubular heart stage, suggesting an important role for the enzyme throughout heart development (Bloch et al. 1999). We have previously found that NO levels are enhanced in embryos from diabetic rats in both early organogenesis and fetal periods (Jawerbaum et al. 2001, 2005, Pustovrh et al. 2005). In the present study, we found an important increase in NOS activity in both the spinal cord and ventricular heart from diabetic fetuses. In addition, we evidenced that NO was able to increase MMP2 activity in fetuses from both control and diabetic rats. Our results suggest that MMPs respond to NO signals in orderto regulate the tissue remodeling that accompanies the rapid growth, differentiation, and structural changes of the fetal organs. Studies that involve MMP2 knockouts or MMP2 overexpression show that the altered activity of this MMP produces changes in the morphology and function of the lung, heart, and pancreas of the developing fetus (Miettinen et al. 2000, Kheradmand et al. 2002, Ratajska & Cleutjens 2002). Interestingly, diabetes produces alterations in the embryonic development mostly associated with increased risks of neonatal respiratory distress, cardiovascular anomalies, and glucose intolerance in adulthood (Piper & Langer 1993, Van Assche et al. 2001). Further research is needed to address whether an abnormal intrauterine environment induces changes in the fetal balance of MMPs that could lead to alterations throughout adult life.
In conclusion, this study demonstrates that NO, overproduced as a result of increased NOS activity in the diabetic feto-placental unit, is able to modulate the activation of MMP2 and MMP9 in these tissues. These results provide further insight into the involvement of NO and MMPs in EMC remodeling during this period of major structural and functional changes in the placenta, and organ development in the fetus, and thus suggest that a dysregulation in MMPs activities may have profound implications in the formation and function of the placenta and fetal organs.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionResultsDiscussionMaterials and MethodsAcknowledgementsReferences |
|---|
Tissue preparation
On day 13.5 of gestation, animals were killed by cervical dislocation and their placentas and fetuses were removed and placed in Petri dishes containing Krebs–Ringer bicarbonate solution (ionic composition: 11 mM glucose, 145 mM Na+, 5.9 mM K+, 2.2 mM Ca2+, 1.2 mM Mg2+, 127 mM Cl– , 25 mM HCO3– , 1.2 mM SO42– , and 1.2 mM PO43– ). Placentas and fetuses were divided into two random groups. One of them was prepared for further histochemical analyses. The placental explants from the other group were incubated as described below: placental tissues were separated into fetal and maternal side under microscope. At this stage, no infiltration of fetal trophoblasts into maternal decidua has taken place, and placenta structures are easily distinguishable. All tissues were incubated for 1 h in a metabolic shaker under an atmosphere of 5% CO2 and 95% O2 at 37 ° C, either with or without sodium nitroprusside (NP 600 µ M; Sigma) or N
-nitro-L-arginine methyl ester hydrochloride (L-NAME 600 µ M; Sigma). Aliquots of incubation medium were frozen at – 70 ° C for further determination of MMPs activities.
NADPH-diaphorase evaluation
Placental and fetal tissues from control and diabetic rats were fixed by immersion in a solution containing 4% paraformaldehyde in 0.1 M phosphate buffer (pH: 7.4) for 24 h. Tissues were immersed in a solution containing 30% sucrose in 0.1 M phosphate buffer and then embedded in optical cutting temperature medium (Sakura Finetek USA, Torrance, CA, USA). Cryostat sections were processed with the NADPH-diaphorase (NADPH-d) histochemical method, which shows the enzyme localization and reflects the degree of NOS activation (Vincent & Kimura 1992, Dellacorte et al. 1995, Morris et al. 1997). Briefly, sections from diabetic and control animals were incubated for 1 h at 37 ° C in a solution containing 0.1% ß-NADPH (1 mg/ml), 0.02% (0.2 mg/ml) nitroblue tetrazolium chloride diluted in 0.1 M phosphate buffer (pH 7.4) and 0.3% Triton X-100 (all reagents from Sigma). Negative control sections were performed omitting the addition of NADPH in the incubation mixture. Sections were mounted on gelatin-coated glass slides and cover slipped with a PBS: glycerol mixture (1:3). Sections were observed and photographed using a Zeiss Axiophot light microscope. The images were digitalized using an image analysis system (Vidas-Kontron, Eching, Germany) and the data were statistically analyzed.
Image analysis
Optical densitometry of sections processed by NADPH-diaphorase was determined in the placentas and fetuses from control and diabetic rats in a Axiophot Zeiss light microscope coupled to a Vidas-Kontron image analyzer. For each experimental condition, the analysis was performed in six sections from different rats.
Zymography
Zymography was performed to evaluate the presence of gelatinase activity as previously described (Woessner & Taplin 1988). In addition, pro-MMPs were also analyzed by zymography, since the exposure to SDS induces changes in pro-MMPs conformation that are associated with their activation. Briefly, 25 µ g protein from fetal and placental tissues (maternal and fetal sides) were subjected to a 7.5% SDS-PAGE, in which 1 mg/ml gelatin (type A from porcine skin) had been incorporated. Following electrophoresis, gels were washed in 30% Triton X-100 for 60 min to remove SDS. Then, the gels were incubated in 50 mM Tris buffer pH 7.4, containing 0.15 mM NaCl and 30 mM CaCl2, for 18 h at 37 ° C. Gels were stained with Coomassie blue and then destained with 10% acetic acid and 30% methanol in water. The areas of proteolytic activity appeared as negative-stained bands in the dark background.
The identities of MMPs were based on their molecular weights and a positive internal control (HT-1080 conditioned medium) that was run in each gel to allow the standardization of the results obtained in the different zymograms.
The enzymatic activity was evaluated using an image analysis program (Sigmagel, Sigma), and expressed as arbitrary densitometric units, which were normalized to the internal control. Data are shown as relative to the value 1 assigned to the mean values for MMP9 in control placenta, and for MMP2 in control fetuses.
Western blotting analysis
Tissues were homogenized in 500 µ l ice-cold lysis buffer (20 mM HCl pH 7.4, 150 mM NaCl, 1% Triton X-100 and 5 µ l protease inhibitor cocktail) and incubated on ice for 2 h. Tissue homogenates were centrifuged at 8000 g (10 000 r.p.m.) for 10 min and the supernatant was removed. Protein concentration was determined by the Bradford assay. Equal amounts of tissue protein extract were subjected to SDS gel electrophoresis on 10% (w/v) polyacrylamide gel under reducing conditions. Proteins were transferred onto nitrocellulose membranes, blocked with 1% BSA (w/v) in Tris-buffered saline Tween-20 (TBST; 0.01 M Tris–HCl, 0.15 M NaCl, and 0.05% (v/v) Tween-20, pH 7.6) for 1.5 h and subsequently incubated with a polyclonal rabbit antibody to either iNOS (1:500) or eNOS (1:500) overnight at 4 ° C. After incubation, the membranes were washed four times with TBST (each time for 10 min), followed by a 1-h incubation with a second goat anti-rabbit antibody conjugated with peroxidase with the ECL Western blotting detection kit (Calbiochem, Darmstadt, Germany) to visualize the iNOS or nNOS bands. The relative intensity of protein signals was quantified by densitometric analysis using the Sigma Gel Program.
Statistical analysis
Results were expressed as means ± S.E.M. Comparisons between groups were performed employing either one-way ANOVA in conjunction with Tukey’s test or Student’s t-test where appropriate. The statistical level of significance was defined as P < 0.05.
|
Acknowledgements |
|---|
|
TopAbstractIntroductionResultsDiscussionMaterials and MethodsAcknowledgementsReferences |
|---|
|
Footnotes |
|---|
|
References |
|---|
|
TopAbstractIntroductionResultsDiscussionMaterials and MethodsAcknowledgementsReferences |
|---|
Akool el S, Kleinert H, Hamada FM, Abdelwahab MH, Forstermann U, Pfeilschifter J & Eberhardt W 2003 Nitric oxide increases the decay of matrix metalloproteinase 9 mRNA by inhibiting the expression of mRNA-stabilizing factor HuR. Molecular and Cellular Biology 23 4901–4916.
Baylis C, Beinder E, Suto T & August P 1998 Recent insights into the roles of nitric oxide and renin-angiotensin in the pathophysiology of preeclamptic pregnancy. Seminars in Nephrology 18 208–230.[Web of Science][Medline]
Blankenship TN & King BF 1994 Identification of 72-kilodalton type IV collagenase at sites of trophoblastic invasion of macaque spiral arteries. Placenta 15 177–187.[Web of Science][Medline]
Bloch W, Fleischmann BK, Lorke DE, Andressen C, Hops B, Hescheler J & Addicks K 1999 Nitric oxide synthase expression and role during cardiomyogenesis. Cardiovascular Engineering 43 675–684.
Brew K, Dinakarpandian D & Nagase H 2000 Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochimica et Biophysic Acta 1477 267–283.
Dellacorte C, Kalinoski DL, Huque T, Wysocki L & Restrepo D 1995 NADPH diaphorase staining suggests localization of nitric oxide synthase within mature vertebrate olfactory neurons. Neuroscience 66 215–225.[CrossRef][Web of Science][Medline]
Eberhardt W, Huwiler A, Beck KF, Walpen S & Pfeilschifter J 2000 Amplification of IL-1 beta-induced matrix metalloproteinase-9 expression by superoxide in rat glomerular mesangial cells is mediated by increased activities of NF-kappa B and activating protein-1 and involves activation of the mitogen-activated protein kinase pathways. Journal of Immunology 165 5788–5797.
Eberhardt W, Akool el S, Rebhan J, Frank S, Beck KF, Franzen R, Hamada FM & Pfeilschifter J 2002 Inhibition of cytokine-induced matrix metalloproteinase 9 expression by peroxisome proliferator-activated receptor alpha agonists is indirect and due to a NO-mediated reduction of mRNA stability. Journal Biological Chemistry 277 33518–33528.
Feng Q, Song W, Lu X, Hamilton JA, Lei M, Peng T & Yee SP 2002 Development of heart failure and congenital septal defects in mice lacking endothelial nitric oxide synthase. Circulation 106 873–879.
Gabbott PL & Bacon SJ 1993 Histochemical localization of NADPH-dependent diaphorase (nitric oxide synthase) activity in vascular endothelial cells in the rat brain. Neuroscience 57 79–95.[CrossRef][Web of Science][Medline]
Galambos C, Ng YS, Ali A, Noguchi A, Lovejoy S, D’Amore PA & DeMello DE 2002 Defective pulmonary development in the absence of heparin-binding vascular endothelial growth factor isoforms. American Journal of Respiratory Cell and Molecular Biology 27 194–203.
Gonzalez E, Jawerbaum A, Sinner D, Pustovrh C, Xaus C, Peralta C, Gomez G, Rosello-Catafau J, Gelpi E & Gimeno M 1999 Evolution of streptozotocin-pancreatic damage in the rat: modulatory effect of endothelins on the nitridergic and prostanoid pathway. Nitric Oxide 3 459–466.[CrossRef][Web of Science][Medline]
Gonzalez E, Rosello-Catafau J, Jawerbaum A, Vela J, Sinner D, Pustovrh C, White V, Xaus C, Peralta C & Gimeno MA 2001 Involvement of inducible isoforms of COX and NOS in streptozotocin-pancreatic damage in the rat: interactions between nitridergic and prostanoid pathway. Prostaglandins Leukotrienes and Essential Fatty Acids 64 311–316.[CrossRef][Web of Science][Medline]
Gu Z, Kaul M, Yan B, Kridel SJ, Cui J, Strongin A, Smith JW, Liddington RC & Lipton SA 2002 S-nitrosyllation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science 297 1186–1190.
Gursoy-Ozdemir Y, Can A & Dalkara T 2004 Reperfusion-induced oxidative/nitrative injury to neurovascular unit after focal cerebral ischemia. Stroke 35 1449–1453.
Hausel P, Latado H, Courjault-Gautier F & Felley-Bosco E 2006 Src-mediated phosphorylation regulates subcellular distribution and activity of human inducible nitric oxide synthase. Oncogene 25 198–206.[Web of Science][Medline]
Jablonka-Shariff A & Olson LM 1997 Hormonal regulation of nitric oxide synthases and their cell-specific expression during follicular development in the rat ovary. Endocrinology 138 460–468.
Jawerbaum A & Gonzalez E 2005 The role of alterations in arachidonic acid metabolism and nitric oxide homeostasis in rat models of diabetes during early pregnancy. Current Pharmaceutical Design 11 1327–1342.[CrossRef][Web of Science][Medline]
Jawerbaum A & González E 2006 Diabetic pregnancies: the challenge of developing in a pro-inflammatory environment. Current Medicinal Chemistry 13 2127–2138.[CrossRef][Web of Science][Medline]
Jawerbaum A, Sinner D, White V, Pustovrh C, Capobianco E, Gimeno MA & Gonzalez ET 2001 Modulation of PGE2 generation in the diabetic embryo: effect of nitric oxide and superoxide dismutase. Prostaglandins Leukotrienes and Essential Fatty Acids 64 127–133.[CrossRef][Web of Science][Medline]
Jawerbaum A, Higa R, White V, Capobianco E, Pustovrh C, Sinner D, Martinez N & González E 2005 Peroxynitrites and impaired modulation of nitric oxide concentrations in embryos from diabetic rats during early organogenesis. Reproduction 130 695–703.
Kheradmand F, Rishi K & Werb Z 2002 Signaling through the EGF receptor controls lung morphogenesis in part by regulating MT1-MMP-mediated activation of gelatinase A/MMP2. Journal of Cell Science 115 839–848.
Kublickiene KR, Cockell AP, Nisell H & Poston L 1997 Role of nitric oxide in the regulation of vascular tone in pressurized and perfused resistance myometrial arteries from term pregnant women. American Journal of Obstetrics and Gynecology 177 1263–1269.[CrossRef][Web of Science][Medline]
Lee TC, Zhao YD, Courtman DW & Stewart DJ 2000 Abnormal aortic valve development in mice lacking endothelial nitric oxide synthase. Circulation 101 2345–2348.
Levine DZ 2006 Hyperfiltration, nitric oxide, and diabetic nephropathy. Current Hypertension Reports 8 153–157.[CrossRef][Web of Science][Medline]
Loesch A, Belai A & Burnstock G 1993 Ultrastructural localization of NADPH-diaphorase and colocalization of nitric oxide synthase in endothelial cells of the rabbit aorta. Cell and Tissue Research 274 539–545.[CrossRef][Web of Science][Medline]
Magness RR, Shaw CE, Phernetton TM, Zheng J & Bird IM 1997 Endothelial vasodilator production by uterine and systemic arteries II. Pregnancy effects on NO synthase expression. American Journal of Physiology 272 H1730–H1740.[Web of Science][Medline]
Miettinen PJ, Huotari M, Koivisto T, Ustinov J, Palgi J, Rasilainen S, Lehtonen E, Keski-Oja J & Otonkoski T 2000 Impaired migration and delayed differentiation of pancreatic islet cells in mice lacking EGF-receptors. Development 127 2617–2627.[Abstract]
Morris BJ, Simpson CS, Mundell S, Maceachern K, Johnston HM & Nolan AM 1997 Dynamic changes in NADPH-diaphorase staining reflect activity of nitric oxide synthase: evidence for a dopaminergic regulation of striatal nitric oxide release. Neuropharmacology 36 1589–1599.[CrossRef][Web of Science][Medline]
Mungrue IN, Gros R, You X, Pirani A, Azad A, Csont T, Schulz R, Butany J, Stewart DJ & Husain M 2002 Cardiomyocyte overexpression of iNOS in mice results in peroxynitrite generation, heart block, and sudden death. Journal of Clinical Investigation 109 735–743.[CrossRef][Web of Science][Medline]
Nakagawa T, Sato W, Sautin YY, Glushakova O, Croker B, Atkinson MA, Tisher CC & Johnson RJ 2006 Uncoupling of vascular endothelial growth factor with nitric oxide as a mechanism for diabetic vasculopathy. Journal of the American Society of Nephrology 17 736–745.
Namkoong S, Lee SJ, Kim CK, Kim YM, Chung HT, Lee H, Han JA, Ha KS & Kwon YG 2005 Prostaglandin E2 stimulates angiogenesis by activating the nitric oxide/cGMP pathway in human umbilical vein endothelial cells. Experimental and Molecular Medicine 37 588–600.[Web of Science][Medline]
Novaro V, Gonzalez E, Jawerbaum A, Rettori V, Canteros G & Gimeno MF 1997 Nitric oxide synthase regulation during embryonic implantation. Reproduction, Fertility and Development 9 557–564.[CrossRef][Medline]
Novaro V, Colman-Lerner A, Ortega FV, Jawerbaum A, Paz D, Lo Nostro F, Pustovrh C, Gimeno MF & Gonzalez E 2001 Regulation of metalloproteinases by nitric oxide in human trophoblast cells in culture. Reproduction, Fertility and Development 13 411–420.[CrossRef][Medline]
Novaro V, Pustovrh C, Colman-Lerner A, Radisky D, Lo Nostro F, Paz D, Jawerbaum A & Gonzalez E 2002 Nitric oxide induces gelatinase A (matrix metalloproteinase 2) during rat embryo implantation. Fertility and Sterility 78 1278–1287.[CrossRef][Web of Science][Medline]
Park JW, Park SJ, Park SH, Kim KY, Chung JW, Chun MH & Oh SJ 2006 Up-regulated expression of neuronal nitric oxide synthase in experimental diabetic retina. Neurobiology of Disease 21 43–49.[CrossRef][Web of Science][Medline]
Peunova N & Enikolopov G 1995 Nitric oxide triggers a switch to growth arrest during differentiation of neuronal cells. Nature 375 68–73.[CrossRef][Medline]
Piper JM & Langer O 1993 Does maternal diabetes delay fetal pulmonary maturity? American Journal of Obstetrics and Gynecology 168 783–786.[Web of Science][Medline]
Portha B, Picon L & Rosselin G 1979 Chemical diabetes in the adult rat as the spontaneous evolution of neonatal diabetes. Diabetologia 17 371–377.[CrossRef][Web of Science][Medline]
Pustovrh C, Jawerbaum A, Sinner D, Pesaresi M, Baier M, Micone P, Gimeno M & Gonzalez ET 2000 Membrane-type matrix metalloproteinase-9 activity in placental tissue from patients with pre-existing and gestational diabetes mellitus. Reproduction, Fertility and Development 12 269–275.[CrossRef][Medline]
Pustovrh C, Jawerbaum A, Sinner D, White V, Capobianco E & Gonzalez E 2002 Metalloproteinase 2 activity and modulation in uterus from neonatal streptozotocin-induced diabetic rats during embryo implantation. Reproduction, Fertility and Development 14 479–485.[CrossRef][Medline]
Pustovrh MC, Jawerbaum A, Capobianco E, White V, Lopez-Costa JJ & Gonzalez E 2005 Increased matrix metalloproteinases 2 and 9 in placenta of diabetic rats at midgestation. Placenta 26 339–348.[CrossRef][Web of Science][Medline]
Ratajska A & Cleutjens JP 2002 Embryogenesis of the rat heart: the expression of collagenases. Basic Research in Cardiology 97 189–197.[CrossRef][Web of Science][Medline]
Rolle U, Shima H & Puri P 2002 Nitric oxide, enhanced by macrophage-colony stimulating factor, mediates renal damage in reflux nephropathy. Kidney International 62 507–513.[CrossRef][Web of Science][Medline]
Salamonsen LA 1999 Role of proteases in implantation. Reviews of Reproduction 4 11–22.[Abstract]
Schonfelder G, John M, Hopp H, Fuhr N, van Der Giet M & Paul M 1996 Expression of inducible nitric oxide synthase in placenta of women with gestational diabetes. FASEB Journal 10 777–784.[Abstract]
Solberg H, Rinkenberger J, Dano K, Werb Z & Lund LR 2003 A functional overlap of plasminogen and MMPs regulates vascularization during placental development. Development 130 4439–4450.
Van Assche FA, Holemans K & Aerts L 2001 Long-term consequences for offspring of diabetes during pregnancy. British Medical Bulletin 60 173–182.
Vincent SR & Kimura H 1992 Histochemical mapping of nitric oxide synthase in the rat brain. Neuroscience 46 755–784.[CrossRef][Web of Science][Medline]
Visse R & Nagase H 2003 Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circulation Research 92 827–839.
Walter I & Schonkypl S 2006 Extracellular matrix components and matrix degrading enzymes in the feline placenta during gestation. Placenta 27 291–306.[CrossRef][Web of Science][Medline]
Woessner JF Jr & Taplin CJ 1988 Purification and properties of a small latent matrix metalloproteinase of the rat uterus. Journal of Biological Chemistry 263 16918–16925.
Wu HH, Cork RJ, Huang PL, Shuman DL & Mize RR 2000 Refinement of the ipsilateral retinocollicular projection is disrupted in double endothelial and neuronal nitric oxide synthase gene knockout mice. Brain Research, Developmental Brain Research 120 105–111.[CrossRef][Medline]
Young SL, Evans K & Eu JP 2002 Nitric oxide modulates branching morphogenesis in fetal rat lung explants. American Journal of Physiology. Lung Cellular and Molecular Physiology 282 L379–L385.
Yu LB, Dong XS, Sun WZ, Zhao DL & Yang Y 2005 Effect of a nitric oxide synthase inhibitor NG-nitro- L-arginine methyl ester on invasion of human colorectal cancer cell line SL-174T. World Journal of Gastroenterology 11 6385–6388.[Medline]
Zhang X, Lin HY, Liu GY, Wang HM, Li QL & Zhu C 2005 Expressions and regulation of endothelial and inducible nitric oxide synthases in mouse uterus during the estrous cycle and early pregnancy. Frontiers in Bioscience 10 3172–3182.[CrossRef][Web of Science][Medline]
Zhao X, Lu X & Feng Q 2002 Deficiency in endothelial nitric oxide synthase impairs myocardial angiogenesis. American Journal of Physiology. Heart and Circulatory Physiology 283 H2371–H2378.
This article has been cited by other articles:
 |
|
 |
|
  G. Osol and M. Mandala Maternal Uterine Vascular Remodeling During Pregnancy Physiology, February 1, 2009; 24(1): 58 - 71. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Deceased 