Published online before print June 6, 2002, doi: 10.1161/01.RES.0000024411.22110.AA
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2002 American Heart Association, Inc.
Cellular Biology |
Hypoxia-Reoxygenation
A Potent Inducer of Apoptotic Changes in the Human Placenta and Possible Etiological Factor in Preeclampsia
From the Department of Obstetrics and Gynaecology (T.-H.H.), Chang Gung Memorial Hospital, Taipei, Taiwan; Department of Anatomy (T.-H.H., J.N.S., G.J.B.) and Department of Obstetrics and Gynaecology (D.S. C.-J.), University of Cambridge, UK.
Correspondence to Graham J. Burton, Department of Anatomy, University of Cambridge, Cambridge CB2 3DY, UK. E-mail gjb2{at}cam.ac.uk
Preeclampsia is a severe disorder of human pregnancy characterized by generalized activation of maternal endothelial cells. Oxidative stress of the placenta is considered a key intermediary step, precipitating deportation of apoptotic fragments into the maternal circulation, but the cause remains unknown. We hypothesize that intermittent placental perfusion, secondary to deficient trophoblast invasion of the endometrial arteries, leads to an ischemia-reperfusion–type insult. We therefore tested whether hypoxia-reoxygenation (H/R) in vitro stimulates apoptosis in human placental tissues compared with controls kept hypoxic or normoxic throughout. After H/R, release of cytochrome c from mitochondria was significantly increased and was associated with intense immunolabeling for active caspase 3 in the syncytiotrophoblast and fetal endothelial cells. There was also increased labeling of syncytiotrophoblastic nuclei for cleaved poly (ADP-ribose) polymerase (PARP), and higher cytosolic concentrations of cleaved PARP fragment were detected by Western blot. Syncytiotrophoblastic nuclei displayed increased chromatin condensation, and a significantly greater percentage was TUNEL positive. These changes were accompanied by increased lactate dehydrogenase release into the medium. Preadministration of the free radical scavenger, desferrioxamine, reduced cytochrome c release and the TUNEL-positive index, suggesting generation of hydroxyl radicals mediates these processes. By contrast, hypoxia alone caused a smaller increase in the TUNEL-positive index, and the majority of syncytiotrophoblastic nuclei displayed karyolysis, whereas normoxic controls remained euchromatic. We conclude that H/R stimulates apoptotic changes within the syncytiotrophoblast, whereas hypoxia principally induces necrosis. The quality of placental perfusion may therefore be a more important factor in the pathophysiology of preeclampsia than the absolute quantity.
Key Words: preeclampsia • oxidative stress • apoptosis • ischemia-reperfusion injury • placenta
This article has been cited by other articles:
 |
|
 |
|
  S. A. Bainbridge, J. M. Roberts, F. von Versen-Hoynck, J. Koch, L. Edmunds, and C. A. Hubel Uric acid attenuates trophoblast invasion and integration into endothelial cell monolayers Am J Physiol Cell Physiol, August 1, 2009; 297(2): C440 - C450. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Scifres and D. M. Nelson Intrauterine growth restriction, human placental development and trophoblast cell death J. Physiol., July 15, 2009; 587(14): 3453 - 3458. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Wang, S. Rana, and S. A. Karumanchi Preeclampsia: The Role of Angiogenic Factors in Its Pathogenesis Physiology, June 1, 2009; 24(3): 147 - 158. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. E. P. Heazell, H. R. Buttle, P. N. Baker, and I. P. Crocker Altered Expression of Regulators of Caspase Activity within Trophoblast of Normal Pregnancies and Pregnancies Complicated by Preeclampsia Reproductive Sciences, December 1, 2008; 15(10): 1034 - 1043. [Abstract] [PDF]
|
|
|
|
|
|
S.-Y. Oh, S.-J. Choi, Kyung Hee Kim, E. Cho, J.-H. Kim, and C.-R. Roh Autophagy-Related Proteins, LC3 and Beclin-1, in Placentas From Pregnancies Complicated by Preeclampsia Reproductive Sciences, November 1, 2008; 15(9): 912 - 920. [Abstract] [PDF]
|
|
|
|
|
|
M. Torricelli, L. Galleri, C. Voltolini, G. Biliotti, P. Florio, M. De Bonis, and F. Petraglia Changes of Placental Kiss-1 mRNA Expression and Maternal/Cord Kisspeptin Levels at Preterm Delivery Reproductive Sciences, October 1, 2008; 15(8): 779 - 784. [Abstract] [PDF]
|
|
|
|
 |
|
 T. Cindrova-Davies, H.-W. Yung, J. Johns, O. Spasic-Boskovic, S. Korolchuk, E. Jauniaux, G. J. Burton, and D. S. Charnock-Jones Oxidative Stress, Gene Expression, and Protein Changes Induced in the Human Placenta during Labor Am. J. Pathol., October 1, 2007; 171(4): 1168 - 1179. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Soleymanlou, A. Jurisicova, Y. Wu, M. Chijiiwa, J. E. Ray, J. Detmar, T. Todros, S. Zamudio, M. Post, and I. Caniggia Hypoxic Switch in Mitochondrial Myeloid Cell Leukemia Factor-1/Mtd Apoptotic Rheostat Contributes to Human Trophoblast Cell Death in Preeclampsia Am. J. Pathol., August 1, 2007; 171(2): 496 - 506. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Tsukimori, H. Nakano, and N. Wake Difference in Neutrophil Superoxide Generation During Pregnancy Between Preeclampsia and Essential Hypertension Hypertension, June 1, 2007; 49(6): 1436 - 1441. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-w. Yung, S. Korolchuk, A. M. Tolkovsky, D. S. Charnock-Jones, and G. J. Burton Endoplasmic reticulum stress exacerbates ischemia-reperfusion-induced apoptosis through attenuation of Akt protein synthesis in human choriocarcinoma cells FASEB J, March 1, 2007; 21(3): 872 - 884. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Belkacemi, S. A. Bainbridge, M. A. Dickinson, G. N. Smith, and C. H. Graham Glyceryl Trinitrate Inhibits Hypoxia/Reoxygenation-Induced Apoptosis in the Syncytiotrophoblast of the Human Placenta: Therapeutic Implications for Preeclampsia Am. J. Pathol., March 1, 2007; 170(3): 909 - 920. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Nevo, N. Soleymanlou, Y. Wu, J. Xu, J. Kingdom, A. Many, S. Zamudio, and I. Caniggia Increased expression of sFlt-1 in in vivo and in vitro models of human placental hypoxia is mediated by HIF-1 Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2006; 291(4): R1085 - R1093. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Bainbridge, L. Belkacemi, M. Dickinson, C. H. Graham, and G. N. Smith Carbon Monoxide Inhibits Hypoxia/Reoxygenation-Induced Apoptosis and Secondary Necrosis in Syncytiotrophoblast Am. J. Pathol., September 1, 2006; 169(3): 774 - 783. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Tjoa, T. Cindrova-Davies, O. Spasic-Boskovic, D. W. Bianchi, and G. J. Burton Trophoblastic Oxidative Stress and the Release of Cell-Free Feto-Placental DNA Am. J. Pathol., August 1, 2006; 169(2): 400 - 404. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.R. Hansson, Y. Chen, J. Brodszki, M. Chen, E. Hernandez-Andrade, J.M. Inman, O.A. Kozhich, I. Larsson, K. Marsal, P. Medstrand, et al. Gene expression profiling of human placentas from preeclamptic and normotensive pregnancies Mol. Hum. Reprod., March 1, 2006; 12(3): 169 - 179. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. R. Armant, B. A. Kilburn, A. Petkova, S. S. Edwin, Z. M. Duniec-Dmuchowski, H. J. Edwards, R. Romero, and R. E. Leach Human trophoblast survival at low oxygen concentrations requires metalloproteinase-mediated shedding of heparin-binding EGF-like growth factor Development, February 15, 2006; 133(4): 751 - 759. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Roberts and H. S. Gammill Preeclampsia: Recent Insights Hypertension, December 1, 2005; 46(6): 1243 - 1249. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Meissner, R. Spranger, M. Lehner, I. Allabauer, W. Rascher, and J. Dotsch Hypoxia-induced leptin production in human trophoblasts does not protect from apoptosis Eur. J. Endocrinol., September 1, 2005; 153(3): 455 - 461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Rajashekhar, A. Loganath, A. C. Roy, S. S. Chong, and Y. C. Wong Hypoxia Up-regulated Angiogenin and Down-regulated Vascular Cell Adhesion Molecule-i Expression and Secretion in Human Placental Trophoblasts Reproductive Sciences, July 1, 2005; 12(5): 310 - 319. [Abstract] [PDF]
|
|
|
|
 |
|
 N. Soleymanlou, I. Jurisica, O. Nevo, F. Ietta, X. Zhang, S. Zamudio, M. Post, and I. Caniggia Molecular Evidence of Placental Hypoxia in Preeclampsia J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 4299 - 4308. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Okazaki, T. Matsuyama, T. Kohno, H. Shindo, T. Koji, Y. Morimoto, and T. Ishimaru Induction of Epithelial Cell Apoptosis in the Uterus by a Mouse Uterine Ischemia-Reperfusion Model: Possible Involvement of Tumor Necrosis Factor-{alpha} Biol Reprod, May 1, 2005; 72(5): 1282 - 1288. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. V. Ashton, G. St. J. Whitley, P. R. Dash, M. Wareing, I. P. Crocker, P. N. Baker, and J. E. Cartwright Uterine Spiral Artery Remodeling Involves Endothelial Apoptosis Induced by Extravillous Trophoblasts Through Fas/FasL Interactions Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 102 - 108. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. T. M. Raijmakers, R. Dechend, and L. Poston Oxidative Stress and Preeclampsia: Rationale for Antioxidant Clinical Trials Hypertension, October 1, 2004; 44(4): 374 - 380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. J. Burton and E. Jauniaux Placental Oxidative Stress: From Miscarriage to Preeclampsia Reproductive Sciences, September 1, 2004; 11(6): 342 - 352. [Abstract] [PDF]
|
|
|
|
 |
|
 I. P. Crocker, D. M. Tansinda, C. J.P. Jones, and P. N. Baker The Influence of Oxygen and Tumor Necrosis Factor-{alpha} on the Cellular Kinetics of Term Placental Villous Explants in Culture J. Histochem. Cytochem., June 1, 2004; 52(6): 749 - 757. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T.-H. Hung, D. S. Charnock-Jones, J. N. Skepper, and G. J. Burton Secretion of Tumor Necrosis Factor-{alpha} from Human Placental Tissues Induced by Hypoxia-Reoxygenation Causes Endothelial Cell Activation in Vitro: A Potential Mediator of the Inflammatory Response in Preeclampsia Am. J. Pathol., March 1, 2004; 164(3): 1049 - 1061. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Bauer, J. Pollheimer, J. Hartmann, P. Husslein, J. D. Aplin, and M. Knofler Tumor Necrosis Factor-{alpha} Inhibits Trophoblast Migration through Elevation of Plasminogen Activator Inhibitor-1 in First-Trimester Villous Explant Cultures J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 812 - 822. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. D. Appleton, G. E. Lash, G. S. Marks, K. Nakatsu, J. F. Brien, G. N. Smith, and C. H. Graham Effect of glucose and oxygen deprivation on heme oxygenase expression in human chorionic villi explants and immortalized trophoblast cells Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2003; 285(6): R1453 - R1460. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. S. Torry, D. Mukherjea, J. Arroyo, and R. J. Torry Expression and Function of Placenta Growth Factor: Implications for Abnormal Placentation Reproductive Sciences, May 1, 2003; 10(4): 178 - 188. [Abstract] [PDF]
|
|