ORCID Profile
0000-0002-5245-718X
Current Organisation
The University of Edinburgh
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Publisher: Cold Spring Harbor Laboratory
Date: 30-05-2022
DOI: 10.1101/2022.05.30.493728
Abstract: Decidualisation is the hormone-dependent process of endometrial remodelling that is essential for fertility and reproductive health. It is characterised by dynamic changes in the endometrial stromal compartment including differentiation of fibroblasts, immune cell trafficking and vascular remodelling. Deficits in decidualisation are implicated in disorders of pregnancy such as implantation failure, intra-uterine growth restriction, and pre-ecl sia. Androgens are key regulators of decidualisation that promote optimal differentiation of stromal fibroblasts and activation of downstream signalling pathways required for endometrial remodelling. We have shown that androgen biosynthesis, via 5α-reductase-dependent production of dihydrotestosterone, is required for optimal decidualisation of human stromal fibroblasts in vitro , but whether this is required for decidualisation in vivo has not been tested. In the current study we used steroid 5α-reductase type 1 (SRD5A1) deficient mice ( Srd5a1-/- mice) and a validated model of induced decidualisation to investigate the role of SRD5A1 and intracrine androgen signalling in endometrial decidualisation. We measured decidualisation response (weight roportion), transcriptomic changes, and morphological and functional parameters of vascular development. These investigations revealed a striking effect of 5α-reductase deficiency on the decidualisation response. Furthermore, vessel permeability and transcriptional regulation of angiogenesis signalling pathways, particularly those that involved vascular endothelial growth factor (VEGF), were disrupted in the absence of 5α-reductase. In Srd5a1-/- mice, injection of dihydrotestosterone co-incident with decidualisation restored decidualisation responses, vessel permeability, and expression of angiogenesis genes to wild type levels. Androgen availability declines with age which may contribute to age-related risk of pregnancy disorders. These findings show that intracrine androgen signalling is required for optimal decidualisation in vivo and confirm a major role for androgens in the development of the vasculature during decidualisation through regulation of the VEGF pathway. These findings highlight new opportunities for improving age-related deficits in fertility and pregnancy health by targeting androgen-dependent signalling in the endometrium.
Publisher: Wiley
Date: 27-04-2016
Publisher: Springer Science and Business Media LLC
Date: 09-11-2016
DOI: 10.1038/SREP36748
Abstract: In women, endometrial breakdown, which is experienced as menstruation, is characterised by high concentrations of inflammatory mediators and immune cells which account for ~40% of the stromal compartment during tissue shedding. These inflammatory cells are known to play a pivotal role in tissue breakdown but their contribution to the rapid scarless repair of endometrium remains poorly understood. In the current study we used a mouse model of menstruation to investigate dynamic changes in mononuclear phagocytes during endometrial repair and remodelling. Menstruation was simulated in MacGreen mice to allow visualisation of CSF1R + mononuclear phagocytes. Immunohistochemistry revealed dynamic spatio-temporal changes in numbers and location of CSF1R-EGFP + cells and Ly6G + neutrophils. Flow cytometry confirmed a striking increase in numbers of GFP + cells during repair (24 h): influxed cells were 66% F4/80 + Gr-1 + and 30% F4/80 − Gr-1 + . Immunostaining identified distinct populations of putative ‘classical’ monocytes (GFP + F4/80 − ), monocyte-derived macrophages (GFP + F4/80 + ) and a stable population of putative tissue-resident macrophages (GFP - F4/80 + ) localised to areas of breakdown, repair and remodelling respectively. Collectively, these data provide the first compelling evidence to support a role for different populations of monocytes/macrophages in endometrial repair and provide the platform for future studies on the role of these cells in scarless healing.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Phoebe Kirkwood.