Regulation of Matrix Metalloproteinase-2 Activity by COX-2-PGE2-pAKT Axis Promotes Angiogenesis in Endometriosis.
Endometriosis is characterized by the ectopic development of the endometrium which relies on angiogenesis. Although studies have identified the involvement of different matrix metalloproteinases (MMPs) in endometriosis, no study has yet investigated the role of MMP-2 in endometriosis-associated angiogenesis. The present study aims to understand the regulation of MMP-2 activity in endothelial cells and on angiogenesis during progression of ovarian endometriosis. Histological and biochemical data showed increased expressions of vascular endothelial growth factor (VEGF), VEGF receptor-2, cycloxygenase (COX)-2, von Willebrand factor along with angiogenesis during endometriosis progression. Women with endometriosis showed decreased MMP-2 activity in eutopic endometrium as compared to women without endometriosis. However, ectopic ovarian endometrioma showed significantly elevated MMP-2 activity with disease severity. In addition, increased MT1MMP and decreased tissue inhibitors of metalloproteinases (TIMP)-2 expressions were found in the late stages of endometriosis indicating more MMP-2 activation with disease progression. In vitro study using human endothelial cells showed that prostaglandin E2 (PGE2) significantly increased MMP-2 activity as well as tube formation. Inhibition of COX-2 and/or phosphorylated AKT suppressed MMP-2 activity and endothelial tube formation suggesting involvement of PGE2 in regulation of MMP-2 activity during angiogenesis. Moreover, specific inhibition of MMP-2 by chemical inhibitor significantly reduced cellular migration, invasion and tube formation. In ovo assay showed decreased angiogenic branching upon MMP-2 inhibition. Furthermore, a significant reduction of lesion numbers was observed upon inhibition of MMP-2 and COX-2 in mouse model of endometriosis. In conclusion, our study establishes the involvement of MMP-2 activity via COX-2-PGE2-pAKT axis in promoting angiogenesis during endometriosis progression.
Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, West Bengal, India.
Sayantan
S
Jana
Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, West Bengal, India.
Kasturi
K
Chatterjee
Spectrum Clinic & Endoscopy Research Institute, Kolkata, West Bengal, India.
Amlan K
AK
Ray
Spectrum Clinic & Endoscopy Research Institute, Kolkata, West Bengal, India.
Pramathes
P
DasMahapatra
Cancer Biology & Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, West Bengal, India.
Snehasikta
S
Swarnakar
D000818:Animals; D051546:Cyclooxygenase 2 / Q000235:genetics*; D015232:Dinoprostone / Q000235:genetics*; D004715:Endometriosis / Q000235:genetics* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000235:genetics*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics
C560823:TIMP2 protein, human; D019716:Tissue Inhibitor of Metalloproteinase-2; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D051058:Oncogene Protein v-akt; D020778:Matrix Metalloproteinase 2; D015232:Dinoprostone
Nat Rev Mol Cell Biol. 2002 Mar;3(3):207-14
11994741
Indian J Biochem Biophys. 2012 Oct;49(5):342-8
23259320
Cell. 2003 Jul 25;114(2):171-80
12887919
J Pineal Res. 2008 May;44(4):439-49
18298469
Hum Reprod. 1998 Jun;13(6):1686-90
9688413
Zhonghua Fu Chan Ke Za Zhi. 2005 Sep;40(9):598-600
16202314
Nat Rev Mol Cell Biol. 2007 Mar;8(3):221-33
17318226
J Clin Invest. 1996 Jul 15;98(2):482-9
8755660
Endocr Relat Cancer. 1999 Jun;6(2):293-301
10731122
Prostaglandins. 1996 Jan;51(1):49-60
8900443
Hum Reprod Update. 2000 Jan-Feb;6(1):45-55
10711829
Biochim Biophys Acta. 2010 Jan;1803(1):103-20
19800930
Semin Reprod Med. 2003 May;21(2):155-64
12917785
Biochem Pharmacol. 2012 Mar 15;83(6):797-804
22227273
Fertil Steril. 2004 May;81(5):1235-9
15136083
Nature. 2005 Jul 7;436(7047):123-7
16001073
Mol Cell Biochem. 2003 Nov;253(1-2):269-85
14619979
Hum Reprod. 2004 Feb;19(2):393-7
14747187
Biochim Biophys Acta. 2010 Jan;1803(1):55-71
20080133
Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4052-7
10737763
Eur J Clin Invest. 1999 Sep;29(9):793-801
10469168
Nat Rev Mol Cell Biol. 2006 May;7(5):359-71
16633338
J Clin Invest. 1997 Jun 15;99(12):2851-7
9185507
Hum Reprod. 2004 Oct;19(10):2180-7
15242997
Obstet Gynecol Int. 2013;2013:859619
23766765
Nature. 2000 Sep 14;407(6801):249-57
11001068
Biochem J. 2003 Sep 15;374(Pt 3):739-45
12755684
Gynecol Endocrinol. 2012 Feb;28(2):134-8
22003899
J Pineal Res. 2010 Sep;49(2):156-68
20609072
Cell. 2011 Sep 16;146(6):873-87
21925313
Semin Cancer Biol. 2009 Oct;19(5):318-28
19482089
Nat Cell Biol. 2000 Oct;2(10):737-44
11025665
Reprod Biomed Online. 2012 May;24(5):496-502
22417665
Nat Rev Endocrinol. 2014 May;10(5):261-75
24366116
J Biol Chem. 1998 Jun 26;273(26):16098-103
9632662
Nat Rev Cancer. 2002 Oct;2(10):795-803
12360282
Int J Cancer. 2010 Sep 1;127(5):1081-95
20027628