8-bromo-cGMP-induced Ca2+-desensitisation mechanisms in human blood vessels – evidence of tissue specificity.

University of Manchester (2010) Proc Physiol Soc 19, C136

Oral Communications: 8-bromo-cGMP-induced Ca2+-desensitisation mechanisms in human blood vessels – evidence of tissue specificity.

A. C. Dordea1, M. Sweeney1, S. C. Robson1, M. J. Taggart1

1. Reproductive and Vascular Biology Group, Newcastle University, Newcastle upon Tyne, United Kingdom.

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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 placental (fetal) circulation develops de novo, whilst the uterine (adult) 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 an useful model for tissue-specific mechanisms of human vascular tone regulation. An elevation in intracellular Ca2+ ([Ca2+]i) in vascular smooth muscle cells leads to constriction via phosphorylation of the myosin light chain (MLC20) by Ca2+-calmodulin-dependent myosin light chain kinase (MLCK). A decrease in [Ca2+]i reduces MLCK activity and, in concert with myosin light chain phosphatase (MLCP) activity, leads to MLC20 dephosphorylation and relaxation. Further molecular signal transduction mechanisms may serve to sensitise or desensitise the myofilaments to changes in [Ca2+]i (1,2). For instance, relaxatory receptor-coupled agonists can stimulate MLCP activity via elevation of cGMP. The aim of this study was to investigate whether cGMP-induced Ca2+-desensitization mechanisms regulate human arterial tone in vitro and also to establish any specificities between vessels of the above two organ systems. Placental (PA) and myometrial arteries (MA) were dissected from biopsies obtained from women (N) at term (N=12 and N=15, respectively) following written informed consent. Arteries were mounted for isometric tension measurement and permeabilised with α-toxin to enable control of [Ca2+] surrounding the myofilaments. Following constriction with maximal [Ca2+] (pCa4.5), arteries were exposed to the non-hydrolysable cGMP analogue 8-bromo-cGMP (10µM) and subsequent contractile responses measured at 5 minute intervals up to 30mins. In PA, 8-br-cGMP induced a relaxation reaching 31 ± 11 % (n=6). In MA, the time-dependent 8-bromo-cGMP-induced relaxation was significantly greater reaching 49 ± 9.7 % (2-way ANOVA, P<0.05, n=7). Thus, the phenomenon of Ca2+-desensitisation occurs in both human artery types. A further assessment of Ca2+-desensitisation was carried out in permeabilised arteries sensitized to supra-basal but submaximal Ca2+ levels (pCa6.7) by a thromboxane analogue U46619 (1µM). In MA, the time-dependent relaxation to 8-br-cGMP (10µM) was again significantly greater than in PA reaching, respectively, 71 ± 5.2 % (n=8) vs. 58 ± 6.7 % (2-way ANOVA, P<0.05, n=6). Thus, these data highlight an altered sensitivity to cGMP between PA and MA and points to differential mechanisms of vascular smooth muscle tone regulation in human vessels of different organs.



Where applicable, experiments conform with Society ethical requirements.

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