During pregnancy, increased uterine blood-flow and efficient placental perfusion is essential for a successful outcome. Despite the essential role of these vascular beds, data on the physiological mechanisms involved in the maintenance of a high-flow/low resistance circulation within the uterus and placenta are limited. The need to fully understand the regulation of blood-flow within the uterine and feto-placental circulations is further highlighted by pathological pregnancies which are characterised by vascular dysfunction within these circulations. Oestrogen and insulin-like growth factor-I (IGF-I) levels increase during pregnancy and correlate with increased uterine blood flow. In vivo and in vitro studies of other vascular beds show that both 17-β oestradiol and IGF-I act as vasodilators. However, surprisingly little is known of their vaso-active effects on human uterine and placental arteries. The aims of the studies described within this thesis, were to investigate, ex vivo, the possible roles of oestrogen and IGF-I in regulating human placental and uterine vascular beds in vivo. Placental chorionic plate arteries and myometrial demonstrated acute vasodilation in response to oestrogen. Vascular bed differences in ER-responsiveness were observed; vasodilation within myometrial arteries was elicited by both oestrogen receptors, ERα and ERβ, although activation of the latter receptor generated a greater response. In contrast, oestrogen-dependent acute vasodilation of placental arteries was via ERβ alone. Furthermore, species differences, between human and rat arteries, were demonstrated in terms of ER-responsiveness. The predominant ER receptor within human arteries studied was ERβ, whilst rat arteries demonstrated a predominantly ERα-mediated mechanism of oestrogen-induced vasodilation. The data presented suggests that within the uterine vascular bed, oestrogen-induced vasodilation involves both an endothelium-dependent and –independent mechanism of action, whilst within the placenta, oestrogen-mediated vasodilation is endothelial-independent. Indeed, data suggests that oestrogen influences the level of intracellular calcium of vascular smooth cells to induce vasodilation of placental arteries.IGF-I did not have a vaso-active effect on chorionic plate arteries isolated from the placenta. However, uterine myometrial arteries exhibited reduced vaso-reactivity in the presence of IGF-I, demonstrated by a depressed response to the vasoconstrictor, U46619. Collectively, these data contribute towards a further understanding of the regulatory mechanisms of the uterine circulation, by identifying oestrogen and IGF-I as possible regulators of the uterine vasculature during pregnancy. Additionally, oestrogen may also have a role in controlling the feto-placental circulation. In the future, targeting ERb may offer a therapeutic strategy for increasing uterine/placental perfusion in pregnancies complicated by vascular dysfunction.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:566583 |
| Date | January 2012 |
| Creators | Corcoran, Jemma Jayne |
| Contributors | Westwood, Melissa; Taggart, Michael |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/oestrogen-and-igfi-regulation-of-placental-and-uterine-bloodflow(0a8bc463-a8e1-45ac-a033-22f5bc89cd26).html |
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