Vascular Signalling Mechanisms in Preeclampsia

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Embargoed until 2024-01-11
Copyright: Luque, Nathan
Introduction: Preeclampsia (PE) causes significant maternal and foetal morbidity and mortality. The causes of PE remain unknown, but uterine or placental vascular endothelial dysfunction/damage are thought to contribute to the pathology of this condition. The potential use pravastatin for the treatment of PE has been reported by multiple studies, however the mechanism(s) behind this is have yet to be elucidated. Aims: To investigate the effect of pravastatin on uterine microvascular endothelial function and caveolae form and distribution in PE Methods: Myometrial radial arterioles from caesarean-section normotensive (NT) and PE patients were incubated with pravastatin (2mM/6h) in vitro. Electron microscopy, immunofluorescence, qPCR and pressure myography were used to characterize caveolae, microdomain signalling, and vessel structure and function. Parallel studies with methyl-β-cyclodextrin (MβCD) (10mM/1h) examined the direct effects of removing membrane cholesterol on vascular function and anatomy. Results: Endothelium-dependent relaxation induced by bradykinin (ByK) was diminished in PE vs NT, associated with loss of nitric oxide (NO) and BKCa mediated dilation, PE vasodilation being SKCa mediated; PE vessels retained vasodilatory response to NO donation. Pravastatin incubation restored PE dilatory function to NT levels by enhancing NO, IKCa and BKCa-mediated components of relaxation; PE vessels exhibited increased stiffness vs NT associated with increased vessel wall cross sectional area; Pravastatin incubation did not affect vessel stiffness in PE or NT; MβCD increased vessel stiffness in NT, whilst PE vessels displayed no change. MEGJ and caveolae/vesicle density was lower in PE than NT; Pravastatin incubation significantly increased MEGJ and lumenal caveolae/vesicle density in PE, while significantly decreasing caveolae and vesicle density throughout NT endothelium; MβCD increased ablumenal caveolae/vesicle density in PE, and produced qualitative reductions in caveolae/vesicles in NT. Cav-1 and IKCa protein expression was decreased in PE vs NT, Cav-1 increased by pravastatin incubation in PE. CAV3 mRNA expression was increased in PE vs NT, but not CAV1, CAV2, CAVIN1 or CAVIN2. Discussion: This thesis reports restored PE dilation to Byk to NT with pravastatin, through mechanisms and structural alterations which are beneficial yet differ considerably from NT, reflecting the altered organisation and regulation of myometrial arteries in this disease state.
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