title: Long-acting progestin-only contraceptives impair endometrial vasculature by inhibiting uterine vascular smooth muscle cell survival.
abstract: Molecular mechanisms responsible for abnormal endometrial vasculature in women receiving long-acting progestin-only contraceptives (LAPCs) are unknown. We hypothesize that LAPCs impair vascular smooth muscle cell (VSMC) and pericyte proliferation and migration producing thin-walled hyperdilated fragile microvessels prone to bleeding. Proliferating cell nuclear antigen (PCNA) and α-smooth muscle actin (αSMA) double-immunostaining assessed VSMC differentiation and proliferation in endometria from women before and after DepoProvera (Depo) treatment and from oophorectomized guinea pigs (OVX-GPs) treated with vehicle, estradiol (E2), medroxyprogesterone acetate (MPA), or E2+MPA. Whole-genome profiling, proliferation, and migration assays were performed on cultured VSMCs treated with MPA or etonogestrel (ETO). Endometrial vessels of Depo-administered women displayed reduced αSMA immunoreactivity and fewer PCNA (+) nuclei among αSMA (+) cells (P < 0.008). Microarray analysis of VSMCs identified several MPA- and ETO-altered transcripts regulated by STAT1 signaling (P < 2.22 × 10(-6)), including chemokine (C-C motif) ligand 2 (CCL2). Both MPA and ETO reduce VSMC proliferation and migration (P < 0.001). Recombinant CCL2 reversed this progestin-mediated inhibition, whereas a STAT1 inhibitor abolished the CCL2 effect. Similarly, the endometria of MPA treated OVX-GPs displayed decreased αSMA staining and fewer PCNA (+) nuclei in VSMC (P < 0.005). In conclusion, LAPCs promote abnormal endometrial vessel formation by inhibiting VSMC proliferation and migration.
authors.affiliation: Department of Obstetrics & Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612; uakayisli@health.usf.edu cjlockwood@health.usf.edu.
authors.forename: Umit A
authors.initials: UA
authors.lastname: Kayisli
authors.affiliation: Department of Obstetrics & Gynecology, College of Medicine, The Ohio State University, Columbus, OH 43210;
authors.forename: Murat
authors.initials: M
authors.lastname: Basar
authors.affiliation: Department of Obstetrics & Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612;
authors.forename: Ozlem
authors.initials: O
authors.lastname: Guzeloglu-Kayisli
authors.affiliation: Department of Obstetrics & Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612;
authors.forename: Nihan
authors.initials: N
authors.lastname: Semerci
authors.affiliation: Department of Pediatric Endocrinology Research, School of Women's & Infants' Health, University of Western Australia, Crawley, WA 6009, Australia; and.
authors.forename: Helen C
authors.initials: HC
authors.lastname: Atkinson
authors.affiliation: Department of Obstetrics & Gynecology, College of Medicine, The Ohio State University, Columbus, OH 43210;
authors.forename: John
authors.initials: J
authors.lastname: Shapiro
authors.affiliation: Department of Obstetrics & Gynecology, College of Medicine, The Ohio State University, Columbus, OH 43210;
authors.forename: Taryn
authors.initials: T
authors.lastname: Summerfield
authors.affiliation: Department of Obstetrics & Gynecology, College of Medicine, The Ohio State University, Columbus, OH 43210;
authors.forename: S Joseph
authors.initials: SJ
authors.lastname: Huang
authors.affiliation: Department of Safety Pharmacology, Bayer HealthCare, GDD-GED-TOX-Safety Pharmacology, 42096 Wuppertal, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Prelle
authors.affiliation: Department of Obstetrics & Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612;
authors.forename: Frederick
authors.initials: F
authors.lastname: Schatz
authors.affiliation: Department of Obstetrics & Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL 33612; uakayisli@health.usf.edu cjlockwood@health.usf.edu.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Lockwood
mesh_terms: D000818:Animals; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D003271:Contraceptive Agents, Female / Q000494:pharmacology*; D017135:Desogestrel / Q000008:administration & dosage / Q000494:pharmacology; D004717:Endometrium / Q000098:blood supply* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000008:administration & dosage / Q000494:pharmacology; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology*; D010052:Ovariectomy; D011372:Progestins / Q000494:pharmacology*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018932:Chemokine CCL2; D003271:Contraceptive Agents, Female; D011372:Progestins; D018809:Proliferating Cell Nuclear Antigen; D050794:STAT1 Transcription Factor; C044815:etonogestrel; D017135:Desogestrel; D017258:Medroxyprogesterone Acetate
keywords: VSMC; abnormal uterine bleeding; impaired vascular maturation; progestin contraceptives; proliferation
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