Assessment of relaxation pathways in isolated arteries from the human uteroplacental unit

Abstract

The successful development of the human fetus during pregnancy depends on a tight regulation of the uteroplacental vasculature in order to allow sufficient provision of oxygen and nutrients from the mother to the placenta and fetus. To accomplish this, the fetoplacental circulation develops de novo, whilst the uterine vasculature undergoes dynamic remodelling. Such distinct features of these circulations suggest that regulation of their vascular function may differ. If so, then in vitro examination of these blood vessels may serve as a useful model for tissue-specific mechanisms of human vascular tone regulation. A reduction in intracellular Ca2+ ([Ca2+]i) in vascular smooth muscle cells leads to an increase of myosin light chain phosphatase (MLCP) activity, which induces myosin light chain dephosphorylation and vasodilation. Further molecular signal transduction mechanisms may serve to desensitise the myofilaments to changes in [Ca2+]i. There is surprisingly little information on the nature of desensitisation to Ca2+ in human myometrial (MA) and placental arteries (PA). Therefore, this study aimed to primarily assess Ca2+-desensitisation mechanisms in MA and PA. Here, we showed (i) that the phenomenon of Ca2+-desensitisation occurred in MA and PA. (ii) That it was promoted by the activation of protein kinase G (PKG) and dependent upon an active MLCP. (iii) That MA displayed greater PKG-mediated Ca2+-desensitisation capabilities compared to PA. In addition, this sensitivity remained greater in MA and PA over the soluble guanylate cylase/PKG axis, but was, surprisingly, reversed at the NO level. Moreover, these differences were not the result of differing expression levels of PKG and PKG-interacting proteins involved in the vasodilatory pathway, as these were similar between the two artery types. These results highlight a variation in vasodilatory responses between MA and PA, which may illustrate a difference in the regulation of vascular tone between the two circulations. Further investigation of the mechanisms involved may prove useful in the development of more tissue-specific therapies.