Abstract
We recently identified sphingosine-1-phosphate (S1P) signaling and the cystic fibrosis transmembrane conductance regulator (CFTR) as prominent regulators of myogenic responsiveness in rodent resistance arteries. However, since rodent models frequently exhibit limitations with respect to human applicability, translation is necessary to validate the relevance of this signaling network for clinical application. We therefore investigated the significance of these regulatory elements in human mesenteric and skeletal muscle resistance arteries. Mesenteric and skeletal muscle resistance arteries were isolated from patient tissue specimens collected during colonic or cardiac bypass surgery. Pressure myography assessments confirmed endothelial integrity, as well as stable phenylephrine and myogenic responses. Both human mesenteric and skeletal muscle resistance arteries (i) express critical S1P signaling elements, (ii) constrict in response to S1P and (iii) lose myogenic responsiveness following S1P receptor antagonism (JTE013). However, while human mesenteric arteries express CFTR, human skeletal muscle resistance arteries do not express detectable levels of CFTR protein. Consequently, modulating CFTR activity enhances myogenic responsiveness only in human mesenteric resistance arteries. We conclude that human mesenteric and skeletal muscle resistance arteries are a reliable and consistent model for translational studies. We demonstrate that the core elements of an S1P-dependent signaling network translate to human mesenteric resistance arteries. Clear species and vascular bed variations are evident, reinforcing the critical need for further translational study.
Highlights
Rodent models are prevalent research tools; yet their human applicability is strikingly limited [1,2] and translation often lags well-behind basic science advancements
We propose that the S1P/CFTR signaling axis [7] prominently regulates myogenic tone in both human mesenteric and human skeletal muscle resistance arteries
Using end-point and quantitative PCR, we demonstrate that human mesenteric resistance arteries express mRNA encoding all critical S1P signaling components, including sphingosine kinase 1 (Sphk1), S1P phosphohydrolase 1 (SPP1) and S1P receptors (S1PR) subtypes 1–3 (Fig 3A; N = 8 separate patient samples)
Summary
Rodent models are prevalent research tools; yet their human applicability is strikingly limited [1,2] and translation often lags well-behind basic science advancements. This divide is remarkably pronounced in the resistance artery research field. The use of isolated human resistance arteries in pressure myography studies, a physiologically relevant means of assessing intact artery function in vitro, is disproportionately sparse. This is ostensibly because tissue samples containing relevant vascular beds are difficult, if not impossible, to routinely obtain. Our dependence on rodent data contributes to the high rate of late-phase clinical trial failures for therapeutics targeting vascular tone and their near-absence in the development pipelines of drug companies
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