P-361 Is HIF-2α involved in pre-menstrual conditioning of the endometrium to ensure optimal repair and prevent heavy menstrual bleeding?

Abstract Study question Does HIF-2α play a key role in pre-menstrual conditioning of the non-pregnant endometrium to optimise menstrual breakdown/repair and prevent heavy bleeding (HMB)? Summary answer HIF-2 was higher secretory women with HMB versus controls, but manipulation mouse model did not impact endometrial breakdown/repair. What is known already Hypoxia inducible factor (HIF) master regulator cellular response hypoxia has two common alpha isoforms (HIF-1α/HIF-2α) overlapping distinct target genes. We revealed that HIF-1α necessary for normal repair. detected human exclusively during phase. The remains undetermined important successful uterine implantation lung vascular remodelling mice. hypothesised required optimising vasculature pre-menstrually ensure appropriate vasoconstriction repair menstruation. design, size, duration examined tissue simulated Hif2α +/- mice provided genetic reduction menses wild-type littermates. also pharmacologically inhibited phase (PT2385 vs vehicle controls). To increase HIF-2, Hif1α were treated HIF stabiliser (DMOG) followed by decreased at –mimicking findings HMB. Participants/materials, setting, methods Human collected (ethically approved consented) from objectively measured (n = 5) controls 4) Western blot. Mouse uterus time progesterone withdrawal (T0, decidualisation) 8h (T8, breakdown) 24h (T24, repair) after withdrawal. Histological blood loss (MBL) quantified. Decidualisation markers RT-qPCR. Endometrial vessel maturity assessed using immunohistochemistry/immunofluorescence. Main results chance protein levels those compared (P < 0.05). Genetic our (Hif2α +/-) no significant differences breakdown (T8) or grade (T24) difference MBL T8 controls. There expression decidualisation (Prlr/Prl3c1) T0 (CD31/α-SMA immunofluorescence staining), presence (pimonidazole immunohistochemistry staining). Pharmacological inhibition showed T24 Increasing via pharmacological stabilisation Hif1α+/- similarly significantly affect contrast Limitations, reasons caution scoring menstruation may be sensitive enough detect subtle changes increased HIF-2α. As delays repair, an additional timepoint 36h better capture any delay as result HIF-2. Wider implications greater than limit loss. Although affected on warrants further investigation fully delineate endometrium. Trial registration number Not applicable