Abstract
Objective
15(S)-Hydroxyeicosatetraenoic acid [15(S)-HETE] and 15(S)-hydroperoxyeicosatetraenoic acid [15(S)-HPETE] are the products of arachidonic acid formed in the 15-lipoxygenase pathway. They have opposing effects on the inflammatory process. The present study was designed to examine the role of these metabolites on angiogenesis, which is critically associated with inflammatory conditions.
Methods
Chick chorio-allantoic membrane (CAM), rat aortic rings and human umbilical vein endothelial cells (HUVECs) in culture were used to study the effect of 15(S)-HETE and 15(S)-HPETE on angiogenesis. Biochemical markers of angiogenesis were analysed by ELISA.
Results
15(S)-HETE increased vessel density in chick CAM, induced sprouting in rat aortic rings and increased endothelial cell–cell contact and formation of tubular network-like structures in HUVECs. Furthermore, it up-regulated the expression of CD31, E-selectin and vascular endothelial growth factor (VEGF) in HUVECs, indicating its pro-angiogenic effect. 15(S)-HPETE, on the other hand, decreased vessel density in chick CAM, down-regulated the expression of E-selectin (<35 %), VEGF (<90 %) and CD31 (<50 %) and did not produce sprouting in aortic rings, suggesting an anti-angiogenic property. 15(S)-HETE-mediated up-regulation of CD 31 and VEGF was reversed by treatment with 15(S)-HPETE.
Conclusion
These results indicate the divergent effects of hydroxy and hydroperoxy products of 15-LOX on angiogenesis, highlighting the role of these products in the co-dependence of inflammation and angiogenesis.
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References
Naldini A, Carraro F. Role of inflammatory mediators in angiogenesis. Curr Drug Targets Inflamm Allergy. 2005;4:3–8.
Barbara W, Peter G. Adhesion molecules: the path to a new understanding of acute inflammation. Physiol Sci. 2000;15:107–13.
William AM. Leukocyte-endothelial cell interactions in the inflammatory response. Lab Invest. 2002;82:521–33.
Hussain SP, Harris CC. Inflammation and cancer: an ancient link with novel potentials. Int J Cancer. 2007;121:2373–80.
Joanna MK, Grietje M. Molecular pathways of endothelial cell activation for (targeted) pharmacological intervention of chronic inflammatory diseases. Curr Vasc Pharmacol. 2005;3:11–39.
David AW, Claire IP. Angiogenesis in the pathogenesis of inflammatory joint and lung diseases. Arthritis Res. 2001;3:147–53.
Peter C. Angiogenesis in health and disease. Nat Med. 2003;9:653–60.
Nikolaos MS, Eleni GT. Role of angiogenesis and vascular remodeling in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2007;2:453–62.
Jeffrey RJ, James DW. The codependence of angiogenesis and chronic inflammation. FASEB J. 1997;11:457–65.
Bharat BA, Gautam S. Inflammation and cancer: how hot is the link? Biochem Pharmacol. 2006;72:1605–21.
Nie D, Honn KV. Cyclooxygenase, lipoxygenase and tumor angiogenesis. Cell Mol Life Sci. 2002;59:799–807.
Xian ZD, Thomas EA. Lipoxygenase and cyclooxygenase metabolism: new insights in treatment and chemoprevention of pancreatic cancer. Mol Cancer. 2003;2:10.
Yamaja SBN, Marie JS. Effects of changes in oxygen tension on vascular and platelet hydroxyacid metabolites. II. Hypoxia increases 15-hydroxyeicosatetraenoic acid, a proangiogenic metabolite. Pediatrics. 1985;75:911–5.
Tang Y, Nie D. Downregulation of vascular endothelial growth factor and induction of tumor dormancy by 15-lipoxygenase-2 in prostate cancer. Int J Cancer. 2009;124:1545–51.
Scott BS, Alan RB. 15-lipoxygenase -2 (15-LOX-2) is expressed in benign prostatic epithelium and reduced in prostate adenocarcinoma. Am J Pathol. 1999;155:235–45.
Reddy R, Reddanna P, Curtis WR. 11-Hydroperoxyeicosatetraenoic acid is the major dioxygenation product of lipoxygenase isolated from hairy root cultures of Solanum tuberosum. Biochem Biophys Res Commun. 1992;189:1349–52.
Nicossia RF, Ottinetti A. Growth of microvessels in serum- free matrix culture of rat aorta: a quantitative assay of angiogenesis in vitro. Lab Invest. 1990;63:115–22.
Kumar VB, Sudhakaran PR. Endothelial cell response to lactate: implications of PAR modification of VEGF. J Cell Physiol. 2007;211:477–85.
Ribatti AD, Basataki M. New model for the study of angiogenesis–antiangiogenesis in the chick embryo chorio allantoic membrane: the gelatin sponge/chorioallantoic membrane assay. J Vasc Res. 1997;34:455–63.
Jaffe EA, Minick CR. Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest. 1973;52:2745–56.
Engvall E, Perlmann P. Enzyme-linked immunosorbent assay (ELISA): quantitative assay of immunoglobulin G. Immunochemistry. 1971;8:871–4.
Kalyan S, Rao GN. 15(S)-Hydroxyeicosatetraenoic acid-induced angiogenesis requires STAT3-dependent expression of VEGF. Cancer Res. 2007;67:4328–36.
Venkatesh KS, Rao GN. 15(S)-Hydroxyeicosatetraenoic acid-induced angiogenesis requires Src-mediated Egr-1-dependent rapid induction of FGF-2 expression. Blood. 2010;115:2105–16.
Baolin Z, Rao GN. 15(S)-Hydroxyeicosatetraenoic acid induces angiogenesis via activation of PI3 K-Akt-mTOR-S6K1 signaling. Cancer Res. 2005;65:7283–91.
Song G, Bao S. The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med. 2005;9:59–71.
Lorraine MS, Isis KM. Enhanced 15-HPETE production during oxidant stress induces apoptosis of endothelial cells. Prostaglandins Other Lipid Mediat. 2005;76:19–34.
Mahipal SV, Reddanna P. Effect of 15-lipoxygenase metabolites, 15-(S)-HPETE and 15-(S)-HETE on chronic myelogenous leukemia cell line K-562: reactive oxygen species (ROS) mediate caspase-dependent apoptosis. Biochem Pharmacol. 2007;74:202–14.
Kiran KYV, Reddanna P. Differential effects of 15-HPETE and 15-HETE on BHK-21 cell proliferation and macromolecular composition. Biochem Biophys Acta. 1993;1167:102–8.
Anil KK, Reddanna P. 15-(S)-HPETE and 15-(S)-HETE effects on acute lymphoblastic leukemia cell line-Jurkat: Activation of Fas mediated death pathway. Biotechnol Appl Biochem. 2007;52:121–33.
Viji RI, Sudhakaran PR. Moduation of cyclooxygenase in endothelial cells by fibronectin: relevance to angiogenesis. J Cell Biol. 2008;105:158–66.
Kumar VB, Sudhakaran PR. Angiogenic effect of laminin involves modulation of cyclooxygenase-2 and prostaglandin levels. Exp Biol Med. 2011;236:44–51.
Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996;86:353–64.
Cesar GR, Andres R. Angiogenesis and ovarian cancer. Clin Transl Oncol. 2009;11:564–71.
Sung HC, Timothy H. Role of prostaglandin E2-dependent angiogenic switch in cyclooxygenase 2-induced breast cancer progression. PNAS. 2004;101:591–6.
Yiping J, Reza D. Anti-angiogenesis effect of the novel anti-inflammatory and pro-resolving lipid mediators. Invest Ophthalmol Vis Sci. 2009;50:4743–52.
Acknowledgments
Financial assistance to Soumya S. J. and Binu S. in the form of JRF from University Grants Commission (UGC) under Research Fellowship in Sciences for Meritorious Students (RFSMS) scheme, New Delhi and Kerala State Council for Science, Technology and Environment (KSCSTE), Thiruvananthapuram and CSIR PDF to Dr. Anil Kumar K. is gratefully acknowledged. We greatly acknowledge the doctors and nursing staffs of Gowreesha Hospital and Anadiyil Hospital for the help received in obtaining umbilical cord for this study.
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Soumya, S.J., Binu, S., Helen, A. et al. Effect of 15-lipoxygenase metabolites on angiogenesis: 15(S)-HPETE is angiostatic and 15(S)-HETE is angiogenic. Inflamm. Res. 61, 707–718 (2012). https://doi.org/10.1007/s00011-012-0463-5
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DOI: https://doi.org/10.1007/s00011-012-0463-5