title: The expression and regulation of adrenomedullin in the human endometrium: a candidate for endometrial repair.
abstract: After menstruation, the endometrium has a remarkable capacity for repair, but the factors involved remain undefined. We hypothesize adrenomedullin (AM) plays a role in this process. Premenstrually progesterone levels decline, stimulating prostaglandin (PG) synthesis, vasoconstriction, and hypoxia. This study aimed to determine 1) AM expression throughout the menstrual (M) cycle and 2) its regulation by PG and hypoxia. Human endometrial biopsies (n = 51) were collected with ethical approval and consent. AM mRNA expression was examined by quantitative RT-PCR and was found to be selectively elevated in endometrium from the menstrual (M) phase (P < 0.001). AM immunohistochemical staining was maximal in M and proliferative (P) endometrium. Culture of secretory, but not P, explants with 100 nm PGF(2α) or hypoxia (0.5% O2) increased AM mRNA (P < 0.05). P explants were induced to increase AM expression using in vitro progesterone withdrawal but required the presence of hypoxia (P < 0.05). Short hairpin sequences against hypoxia-inducible factor-1α (HIF-1α) inhibited AM hypoxic up-regulation but did not alter PGF(2α)-induced expression. The AM receptor was immunolocalized to endothelial cells in both lymphatic and blood vessels. Conditioned medium from PGF(2α)-treated cells increased endothelial cell proliferation and branching (P < 0.05). This was abolished by AM receptor antagonists. In conclusion, AM is elevated at the time of endometrial repair and induces both angiogenesis and lymphangiogenesis by stimulating endothelial cell proliferation and tube formation. In the human endometrium, AM expression is up-regulated by two mechanisms: a HIF-1α-mediated hypoxic induction and a HIF-1α-independent PGF(2α) pathway. These physiological mechanisms may provide novel therapeutic targets for disorders such as heavy menstrual bleeding.
authors.affiliation: Centre for Reproductive Biology, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Maybin
authors.forename: Sharon
authors.initials: S
authors.lastname: Battersby
authors.forename: Nikhil
authors.initials: N
authors.lastname: Hirani
authors.forename: Leonid L
authors.initials: LL
authors.lastname: Nikitenko
authors.forename: Hilary O D
authors.initials: HO
authors.lastname: Critchley
authors.forename: Henry N
authors.initials: HN
authors.lastname: Jabbour
mesh_terms: D053607:Adrenomedullin / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D015687:Cell Hypoxia; D002460:Cell Line; D049109:Cell Proliferation; D015237:Dinoprost / Q000378:metabolism; D004717:Endometrium / Q000098:blood supply / Q000166:cytology / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors / Q000235:genetics; D042583:Lymphangiogenesis; D008597:Menstrual Cycle / Q000378:metabolism*; D008875:Middle Aged; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D058265:Receptors, Adrenomedullin / Q000037:antagonists & inhibitors / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000378:metabolism
chemical_list: C507862:ADM protein, human; D043925:Angiogenesis Inducing Agents; D051793:Hypoxia-Inducible Factor 1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D058265:Receptors, Adrenomedullin; D011982:Receptors, Prostaglandin; D053607:Adrenomedullin; D015237:Dinoprost