This Article Full Text Full Text (PDF) All Versions of this Article: 34/3/776    most recent 01.STR.0000055763.76479.E6v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brault, S. Articles by Chemtob, S. Search for Related Content PubMed PubMed Citation Articles by Brault, S. Articles by Chemtob, S. Related Collections Ischemic biology - basic studies Pathology of Stroke Endothelium/vascular type/nitric oxide

(Stroke. 2003;34:776.)
© 2003 American Heart Association, Inc.

Original Contributions

Selective Neuromicrovascular Endothelial Cell Death by 8-Iso-Prostaglandin F₂

Possible Role in Ischemic Brain Injury

Sonia Brault, MSc; Ana Katherine Martinez-Bermudez, MSc; Anne Marilise Marrache, BSc; Fernand Gobeil, Jr, PhD; Xin Hou, MD, PhD; Martin Beauchamp, BSc; Christiane Quiniou, MSc; Guillermina Almazan, PhD; Christian Lachance, MD; Jackson Roberts, II, MD, PhD; Daya R. Varma, MD, PhD Sylvain Chemtob, MD, PhD

From the Centre de Recherche de l’Hôpital Sainte-Justine, Department of Pediatrics and Pharmacology, Université de Montréal, Montréal, Québec, Canada (S.B., A.K.M-B., A.M.M., F.G., X.H., M.B., C.Q., C.L., S.C.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (S.B., A.K.M-B., A.M.M., G.A., D.R.V., S.C.); and Department of Pharmacology and Medicine, Vanderbilt University, Nashville, Tenn (J.R.).

Correspondence to Sylvain Chemtob, MD, PhD, FRCPC, Departments of Pediatrics, Ophthalmology, and Pharmacology, Research Center, Hôpital Sainte-Justine, 3175 Côte Sainte-Catherine, Montreal, Quebec H3T 1C5, Canada. E-mail sylvain.chemtob{at}umontreal.ca

Background and Purpose— Free radical-induced peroxidation is an important factor in the genesis of hypoxic-ischemic encephalopathy, including that of the preterm infant. Isoprostanes are major peroxidation products. Since microvascular dysfunction seems to contribute to ischemic encephalopathies, we studied the cytotoxicity of 8-iso-prostaglandin F₂ (PGF₂) on cerebral microvascular cells.

Methods— Microvascular endothelial, astroglial, and smooth muscle cells from newborn brain were cultured. The cytotoxicity of 8-iso-PGF₂ on these cells was determined by MTT assays and lactate dehydrogenase (LDH) release, propidium iodide incorporation, and DNA fragmentation (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling [TUNEL]). In addition, effects of intraventricular injections of 8-iso-PGF₂ and possible involvement of thromboxane in 8-iso-PGF₂-induced cytotoxicity were determined.

Results— 8-Iso-PGF₂ induced time- and concentration-dependent endothelial cell death (EC₅₀=0.1 nmol/L) but exerted little effect on smooth muscle and astroglial cells; endothelial cell death seemed mostly of oncotic nature (propidium iodide incorporation and LDH release). Cell death was associated with increased endothelial thromboxane A₂ (TXA₂) formation and was prevented by TXA₂ synthase inhibitors (CGS12970 and U63557A); TXA₂ mimetics U46619 and I-BOP also caused endothelial cell death. Intraventricular injection of 8-iso-PGF₂ induced periventricular damage, which was attenuated by CGS12970 pretreatment.

Conclusions— These data disclose a novel action of 8-iso-PGF₂ involving TXA₂ in oxidant stress-induced cerebral microvascular injury and brain damage.

Key Words: apoptosis • brain damage • necrosis • oxidants • thromboxanes • white matter

This article has been cited by other articles:

				R. A. Benndorf, E. Schwedhelm, A. Gnann, R. Taheri, G. Kom, M. Didie, A. Steenpass, S. Ergun, and R. H. Boger Isoprostanes Inhibit Vascular Endothelial Growth Factor-Induced Endothelial Cell Migration, Tube Formation, and Cardiac Vessel Sprouting In Vitro, As Well As Angiogenesis In Vivo via Activation of the Thromboxane A2 Receptor: A Potential Link Between Oxidative Stress and Impaired Angiogenesis Circ. Res., October 24, 2008; 103(9): 1037 - 1046. [Abstract] [Full Text] [PDF]

				C. Quiniou, P. Sapieha, I. Lahaie, X. Hou, S. Brault, M. Beauchamp, M. Leduc, L. Rihakova, J.-S. Joyal, S. Nadeau, et al. Development of a Novel Noncompetitive Antagonist of IL-1 Receptor J. Immunol., May 15, 2008; 180(10): 6977 - 6987. [Abstract] [Full Text] [PDF]

				S. Brault, F. Gobeil Jr., A. Fortier, J.-C. Honore, J.-S. Joyal, P. S. Sapieha, A. Kooli, E. Martin, P. Hardy, A. Ribeiro-da-Silva, et al. Lysophosphatidic acid induces endothelial cell death by modulating the redox environment Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2007; 292(3): R1174 - R1183. [Abstract] [Full Text] [PDF]

				G. Cambonie, B. Comte, C. Yzydorczyk, T. Ntimbane, N. Germain, N. L. O. Le, P. Pladys, C. Gauthier, I. Lahaie, D. Abran, et al. Antenatal antioxidant prevents adult hypertension, vascular dysfunction, and microvascular rarefaction associated with in utero exposure to a low-protein diet Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2007; 292(3): R1236 - R1245. [Abstract] [Full Text] [PDF]

				P. Wentzel and U. J. Eriksson Ethanol-Induced Fetal Dysmorphogenesis in the Mouse Is Diminished by High Antioxidative Capacity of the Mother Toxicol. Sci., August 1, 2006; 92(2): 416 - 422. [Abstract] [Full Text] [PDF]

				C. Quiniou, F. Sennlaub, M. H. Beauchamp, D. Checchin, I. Lahaie, S. Brault, F. Gobeil Jr., M. Sirinyan, A. Kooli, P. Hardy, et al. Dominant Role for Calpain in Thromboxane-Induced Neuromicrovascular Endothelial Cytotoxicity J. Pharmacol. Exp. Ther., February 1, 2006; 316(2): 618 - 627. [Abstract] [Full Text] [PDF]

				P. Pladys, F. Sennlaub, S. Brault, D. Checchin, I. Lahaie, N. L. O. Le, K. Bibeau, G. Cambonie, D. Abran, M. Brochu, et al. Microvascular rarefaction and decreased angiogenesis in rats with fetal programming of hypertension associated with exposure to a low-protein diet in utero Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2005; 289(6): R1580 - R1588. [Abstract] [Full Text] [PDF]

				R. J. Gonzales, A. A. Ghaffari, S. P. Duckles, and D. N. Krause Testosterone treatment increases thromboxane function in rat cerebral arteries Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H578 - H585. [Abstract] [Full Text] [PDF]

				J.-L. Cracowski and O. Ormezzano Isoprostanes, emerging biomarkers and potential mediators in cardiovascular diseases Eur. Heart J., October 1, 2004; 25(19): 1675 - 1678. [Full Text] [PDF]

				H. Shibata, T. Nabika, H. Moriyama, J. Masuda, and S. Kobayashi Correlation of NO Metabolites and 8-Iso-Prostaglandin F2a With Periventricular Hyperintensity Severity Arterioscler Thromb Vasc Biol, September 1, 2004; 24(9): 1659 - 1663. [Abstract] [Full Text] [PDF]