The extracellular signal‐regulated kinase 1/2 triggers angiogenesis in human ectopic endometrial implants by inducing angioblast differentiation and proliferation. (16th September 2017)

• Record Type: Journal Article
• Authors: Arlier, Sefa; Murk, William; Guzeloglu‐Kayisli, Ozlem; Semerci, Nihan; Larsen, Kellie; Tabak, Mehmet S.; Arici, Aydin; Schatz, Frederick; Lockwood, Charles J.; Kayisli, Umit A.
• Is Part Of: American journal of reproductive immunology. Volume 78:Number 6(2017)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2017-09-16
• Subjects: angioblast -- angiogenesis -- endometriosis -- ERK1/2 MAPK -- peritoneal fluid -- proliferation; Human reproduction -- Immunological aspects -- Periodicals; 616.69206
• DOI: 10.1111/aji.12760
• Languages: English
• ISSNs: 1046-7408

Abstract

Abstract : Problem: The role of extracellular signal‐regulated kinase (ERK)1/2‐mediated angiogenesis during endometriotic nidation is unknown. We posit that ERK1/2‐induced angioblast differentiation and proliferation promotes ectopic endometrial angiogenesis. Methods of study: Human eutopic and ectopic endometria were immunostained for total‐ (T‐) or phosphorylated‐ (P‐) ERK1/2 or double‐immunostained for P‐ERK1/2‐CD34 and PCNA‐CD34. Estradiol (E2 ), cytokines, normal peritoneal fluid (NPF) or endometriotic peritoneal fluid (EPF) ±PD98059, an ERK1/2 inhibitor, treaded primary human endometrial endothelial cells (HEECs) were evaluated by T‐/P‐ERK1/2 immunoblotting, MTT viability and tube formation assays. Results: HEECs exhibited higher endothelial P‐ERK1/2 immunoreactivity in ectopic vs eutopic endometria. Double‐immunostained ectopic endometria displayed abundant CD34‐positive angioblasts exhibiting strong P‐ERK1/2 and PCNA immunoreactivity. EPF and vascular growth factor (VEGF)‐A significantly increased HEEC proliferation and P‐ERK1/2 levels. PD98059 reduced basal, EPF, and VEGF‐induced HEEC proliferation and promoted vascular stabilization following tube formation. Conclusion: Enhanced ERK1/2 activity in angioblasts by such peritoneal factors as VEGF, E2 induces proliferation to trigger ectopic endometrial angiogenesis. Abstract : Increased ERK1/2 phosphorylation (P‐ERK1/2) is involved in endothelial progenitor cell (angioblast) differentiation and proliferation in endometriosis. Several individual cells (asterisks) and cell clusters of vascular like structures (presumptive vessels; arrows) display the strongest P‐ERK1/2 immunoreactivity in the ectopic endometrium, whereas endothelial cells in distal to ectopic tissue (arrowheads) exhibit weak to moderate P‐ERK1/2 immunoreactivity (A, B). CD34, an angioblast marker and P‐ERK1/2 double immunostaining is seen in ectopic endometrial specimens (C‐E) with stronger P‐ERK1/2 (brown) immunoreactivity in CD34 immunoreactive (red) endothelial progenitor cells (arrows; C or D) vs. mature vascular endothelial cells (arrowheads in C or E). Representative photomicrographs of CD34 and PCNA double immunostained ectopic endometrial specimens display stronger co‐expression of CD34 (red) and PCNA (brown) in endothelial progenitor cells (arrows; F) than in mature vascular endothelial cells (arrowheads; G), indicating proliferative nature of this CD34 immunoreactive angioblasts.