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The extracellular signal‐regulated kinase 1/2 triggers angiogenesis in human ectopic endometrial implants by inducing angioblast differentiation and proliferation
Author(s) -
Arlier Sefa,
Murk William,
GuzelogluKayisli Ozlem,
Semerci Nihan,
Larsen Kellie,
Tabak Mehmet S.,
Arici Aydin,
Schatz Frederick,
Lockwood Charles J.,
Kayisli Umit A.
Publication year - 2017
Publication title -
american journal of reproductive immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.071
H-Index - 97
eISSN - 1600-0897
pISSN - 1046-7408
DOI - 10.1111/aji.12760
Subject(s) - angiogenesis , vascular endothelial growth factor , cd34 , mapk/erk pathway , biology , endometrium , kinase , endocrinology , medicine , cancer research , chemistry , microbiology and biotechnology , stem cell , vegf receptors
Problem The role of extracellular signal‐regulated kinase ( ERK )1/2‐mediated angiogenesis during endometriotic nidation is unknown. We posit that ERK 1/2‐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‐) ERK 1/2 or double‐immunostained for P‐ ERK 1/2‐ CD 34 and PCNA ‐ CD 34. Estradiol (E 2 ), cytokines, normal peritoneal fluid ( NPF ) or endometriotic peritoneal fluid ( EPF ) ± PD 98059, an ERK 1/2 inhibitor, treaded primary human endometrial endothelial cells ( HEEC s) were evaluated by T‐/P‐ ERK 1/2 immunoblotting, MTT viability and tube formation assays. Results HEEC s exhibited higher endothelial P‐ ERK 1/2 immunoreactivity in ectopic vs eutopic endometria. Double‐immunostained ectopic endometria displayed abundant CD 34‐positive angioblasts exhibiting strong P‐ ERK 1/2 and PCNA immunoreactivity. EPF and vascular growth factor ( VEGF )‐A significantly increased HEEC proliferation and P‐ ERK 1/2 levels. PD 98059 reduced basal, EPF , and VEGF ‐induced HEEC proliferation and promoted vascular stabilization following tube formation. Conclusion Enhanced ERK 1/2 activity in angioblasts by such peritoneal factors as VEGF , E 2 induces proliferation to trigger ectopic endometrial angiogenesis.