Can Kynurenine Pathway Manipulation Ameliorate Maternal Vascular Features of Preeclampsia?

UoM administered thesis: Phd

Abstract

Preeclampsia (PE), a hypertensive disorder of pregnancy, is a major contributor to morbidity and mortality for pregnant women and their offspring. Severe maternal hypertension is a risk factor for cerebrovascular accident and a leading indication for preterm delivery, which can have serious and lifelong consequences. Dysfunction of small resistance arteries, which demonstrate increased vasoconstrictor sensitivity and impaired endothelium-dependent relaxation, is a key contributor to maternal systemic vascular resistance and hypertension in PE. Kynurenine (Kyn) is an endogenous vasorelaxant derived from tryptophan catabolism via the Kyn pathway. Activation of the Kyn pathway by infection and inflammation contributes to the development of systemic hypotension. Kyn has direct vasorelaxant effects on arteries from several species and reduces systemic blood pressure in rats. This thesis tested the hypothesis that Kyn can ameliorate dysfunction in arteries from women with PE. The effects of Kyn in maternal omental and myometrial resistance arteries were investigated using isometric myography. In arteries from both maternal vascular beds, Kyn reduced sensitivity to a thromboxane mimetic (U46619) and induced substantial and reproducible relaxation of preconstricted arteries. Vasorelaxant effects were independent of the endothelium and wholly mediated via large-conductance calcium-activated potassium (BKCa) channels, a previously unrecognised mechanism for Kyn activity. Effects of Kyn were replicated, albeit slightly reduced, in omental arteries from women with PE, suggesting the potential for therapeutic application of Kyn to cause vasorelaxation in PE. A pilot study in normotensive Sprague Dawley rats determined treatment with Kyn or its precursor tryptophan (100 mg/kg/day) in drinking water is feasible, tolerable, and without any immediate maternal or fetal harm. Increased [Kyn] in fetal plasma following maternal Kyn treatment indicates efficacy of treatment for increasing Kyn bioavailability. In mesenteric arteries isolated from pregnant rats, Kyn caused a large reduction in U46619 sensitivity and induced BKCa mediated relaxation of preconstricted arteries; thus, Sprague Dawley rats recapitulate the vascular effects of Kyn observed in human arteries and are a suitable animal model for future investigations. This thesis provides compelling evidence indicating the vasorelaxant effects of Kyn may offer potential to develop a new clinical intervention for the treatment of hypertension in PE. As the next step towards clinical translation, future work will investigate the effects of Kyn pathway manipulation on maternal hypertension in an in vivo model of PE.

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Original languageEnglish
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Award date1 Aug 2020