- Title
- The role of intrauterine tissue renin-angiotensin systems in pregnancy and reproductive health
- Creator
- Delforce, Sarah Jane
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2019
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- This thesis will describe the role of the intrauterine renin-angiotensin systems (RASs) in the physiological regulation of intrauterine tissues. Tissue RASs play a role in proliferation, angiogenesis, migration, invasion and fibrosis through the stimulation of intracellular signaling pathways and production of growth factors. The intrauterine environment, both pregnant and non-pregnant, relies on growth and vascularisation during the menstrual cycle in the transformation of the endometrium to a decidua and in placentation. My research investigated the role of intrauterine tissue RASs in the: stimulation of growth and vascularisation of the early gestation placenta; pathology of fetal growth restriction; regulation of the growth and vascularisation of the endometrium and how this is perturbed in endometrial pathology (endometrial cancer). The work in this thesis identified a critical role for oxygen regulation of the placental RAS in early placental development. The physiological low oxygen tension in the first trimester of gestation stimulates expression of pro-angiogenic/pro-proliferative components of the RAS (namely the angiotensin II type 1 receptor, AGTR1) in both a first trimester extravillous trophoblast cell line (HTR-8/SVneo) as well as first trimester chorionic villi explants. Furthermore, in HTR-8/SVneo cells, I identified that signalling through the upregulated AT1 receptor promoted pro-angiogenic signalling (through vascular endothelial growth factor, plasminogen activator inhibitor-1 and angiopoietin 2). This upregulation in pro-angiogenic signalling translated to increased tube formation in human umbilical vein endothelial cells, which is reflective of angiogenic capacity. Furthermore, these oxygen regulated changes in the placental RAS do not appear to be regulated by oxygen sensitive miRNAs in CVEs in the same way as we have observed HTR-8/SVneo cells. This work highlights the critical interaction between physiological oxygen tension, the RAS and placental development. In investigating the expression of the placental RAS in pregnancies compromised by FGR, we identified novel potential therapeutic targets that might mediate the pathogenesis of FGR. I demonstrated that there is a significant decrease in two key enzymes, neprilysin and angiotensin converting enzyme 2 (ACE2), which are key regulators of converting the vasoconstrictor Angiotensin II (Ang II) to the vasodilatory, Ang-(1-7) in placentae associated with FGR. I suggest that there is potential to therapeutically target the imbalance in Ang II/Ang-(1-7) and over-activation of the vasoconstrictor arm of the RAS by enhancing the opposing ACE2/Ang–(1-7) pathway, through increased production or direct treatment with Ang–(1-7), to promote placental and maternal blood flow and efficient exchange of nutrients and gases. Lastly, this thesis demonstrates that the pro-angiogenic/pro-proliferative RAS pathway ((pro)renin receptor, Ang II type 1 receptor and angiotensin converting enzyme) is overexpressed in endometrial cancer. It also provides further insight to the molecular signalling pathways that may be involved in endometrial angiogenesis, proliferation and invasion (through transforming growth factor-b signalling) as well as tumourigenesis. Furthermore, this study highlights the potential for existing drugs that inhibit the RAS, which are used to treat hypertension, to be repositioned as treatments for endometrial cancer. Overall, the work in this thesis has greatly added to the body of information highlighting the role of tissue RAS in the regulation of tissue growth and vascularisation. It stressed particularly, the role of the placental RAS in early placental development as well as regulation of blood flow in the third trimester. The overexpression of proangiogenic/pro-proliferative RAS components in endometrial cancer also emphasizes the role of tissue RAS in growth and vascularisation. Lastly, the review comparing the parallels between placentation, tumour development and the RAS shows the importance of interdisciplinary study in identifying physiological and pathophysiological RAS function.
- Subject
- intrauterine renin-angiotensin systems; early gestation placenta; vascularisation; endometrial cancer; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1400404
- Identifier
- uon:34766
- Rights
- Copyright 2019 Sarah Jane Delforce
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 10 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 225 KB | Adobe Acrobat PDF | View Details Download |