Regulation of Matrix Metalloproteinase-2 Activity by COX-2-PGE2-pAKT Axis Promotes Angiogenesis in Endometriosis

被引：80
作者：
Jana, Sayantan [1 ]
Chatterjee, Kasturi [1 ]
Ray, Amlan K. [2 ]
DasMahapatra, Pramathes [2 ]
Swarnakar, Snehasikta [1 ]
机构：
[1] CSIR, Indian Inst Chem Biol, Canc Biol & Inflammatory Disorder Div, Kolkata, W Bengal, India
[2] Spectrum Clin & Endoscopy Res Inst, Kolkata, W Bengal, India
来源：
PLOS ONE | 2016年 / 11卷 / 10期
关键词：
ENDOTHELIAL GROWTH-FACTOR; TISSUE INHIBITORS; PERITONEAL-FLUID; VEGF; MATRIX-METALLOPROTEINASE-9; MACROPHAGES; ACTIVATION; EXPRESSION; MELATONIN; CURCUMIN;
D O I：
10.1371/journal.pone.0163540
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
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-PGE2pAKT axis in promoting angiogenesis during endometriosis progression.
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页数：18
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