The endometrium is the tissue lining the inner cavity of the uterus in which nidation and pregnancy maintenance occurs. To date, there are no physiological models that recapitulate the human endometrial microenvironment; thus, our understanding of the role of the vasculature in regulating endometrial reproductive processes remains largely unknown. âOrgans-on-a-Chipâ (OoC) models are compartmentalized microfluidic cultures of heterotypic cells that better approximate the human in vivo conditions. Herein, we engineered and established an OoC model of the human endometrial perivascular stroma to test the hypothesis that the endometrial vascular endothelium plays a role in regulating both normal reproduction function and disease pathogenesis. We examined the crosstalk between prolonged cultures of human endometrial endothelial cells and stromal fibroblasts under hormonal and physiological signals. Our studies demonstrated that shear stress-induced secretion of specific endothelial cell-derived prostaglandins enhances perivascular response to progesterone via a paracrine mechanism. Altogether, these translational findings show that the endometrial vascular endothelium plays a key physiologic role during the initiation of perivascular decidualization in the human endometrium. Furthermore, vascular dysfunction alters the immune-endocrine inflammatory axis of the endometrium and contributes to the pathogenesis of endometrial disorders. Specifically, endocrine disruptors such as the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) promoted an enhanced immune cell recruitment. Identification of specific inflammatory mediators necessary during endometrial reproductive processes may have clinical utility as therapeutic targets for reproductive disorders such as infertility, endometriosis, preeclampsia and poor pregnancy outcomes.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03262018-230902 |
| Date | 12 April 2018 |
| Creators | Gnecco, Juan Sebastian |
| Contributors | Pampee Young MD, PhD., Pampee Young MD, PhD., Andries Zijlstra, PhD, Andries Zijlstra, PhD, Lisa McCawley, PhD, Lisa McCawley, PhD, David Aronoff, MD, David Aronoff, MD, Kevin Osteen, PhD, Kevin Osteen, PhD |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-03262018-230902/ |
| Rights | restrictsix, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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