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. Wholegenome 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.progestin contraceptives | abnormal uterine bleeding | VSMC | impaired vascular maturation | proliferation

Uterine Gα q/11 signaling, in a progesterone‐dependent manner, critically regulates the acquisition of uterine receptivity in the female mouse

“…Differences in the circular muscle (CM) were not clearly apparent but could not be ruled out. Myometrial hypertrophy is P4 dependent, and a-SMA levels are reduced in endometrial vasculature following progestin treatment (30). Therefore, to determine whether the reduced hypertrophy was due to changes in a-SMA expression, a-SMA was assessed in CTRL and KO uteri; however, striking differences were not apparent, suggesting that altered a-SMA expression does not underlie the phenotype (Fig.…”

Endometrial breakdown with sustained progesterone release involves NF-κB-mediated functional progesterone withdrawal in a mouse implant model

“…Irregular bleeding arises from endometrial hemostasis and structural impairments due to inflammation and oxygen stress. The aberrant activities of proteins that regulate angiogenesis appear to contribute to breakthrough bleeding (Lockwood, ; Kayisli et al, ; Hapangama and Bulmer, ), although the exact molecular mechanism is not yet fully elucidated. The use of progesterone subcutaneous implants in mice and guinea pigs represent a convenient model for the investigation of the mechanisms underlying irregular endometrial tissue breakdown or abnormal bleeding in women using LTPOCs (Morison et al, ; Alvarez Gonzalez et al, ; Krikun et al, ).…”

“…PGR antagonists like RU486 can be used to mimic this phenomenon, thus eliciting a functional progesterone withdrawal that reverses the network of signaling events sustaining progesterone's effects, resulting in physiological or pathological phenomena including menstruation, labor, preterm labor, and abortion. The biochemical changes that repress transcriptional activity of PGR involve interactions between PGR and the transcription factor nuclear factor kappa-B (NFkB) (Kalkhoven et al, 1996;Hardy et al, 2006); increased expression of PGR-A or PGR-C, which inhibits the activity of PGR-B (Condon et al, 2006;Merlino et al, 2007); altered expression of PGR co-regulators (Condon et al, 2003;Dong et al, 2009); increased progesterone metabolism (Mahendroo et al, 1996(Mahendroo et al, , 1999; activation of progestin membrane receptors (Karteris et al, 2006); reduction in PGR abundance by microRNA-200a (Williams et al, 2012); or up-regulation of FKBP51 expression (Guzeloglu Kayisli et al, 2015).…”

Remodeling of endometrial vascular system in woman of reproductive age in normal and pathological condition (a review)

“…У женщин с аномальными маточными кровотечениями по типу гиперполименореи выявлено меньшее количество перицитов в фазу пролиферации без необходимого уменьшения их числа в фазу секреции, в то время как сама площадь сосудистого русла не отличалась от контрольной группы [32]. Длительное применение гестагенов также приводит к нарушению пролиферации и миграции перицитов с формированием тонкостенных сосудов, более склонных к кровотечениям [33].…”