Abstract 10970: From Rodents to Man: Confirmation of S1P Signalling as a Central Regulator of Myogenic Responsiveness in Human Resistance Arteries
Pre-capillary resistance arteries are the primary regulators of total peripheral resistance and hence, tissue perfusion and systemic blood pressure. Their tone is determined by their smooth muscle cells’ (i.e. myogenic) ability to adjust their diameter to transmural pressure. In rodents, sphingosine-1-phosphate (S1P) signalling is a key regulator of this response and targeted by several diseases involving microvascular dysfunction (heart failure, diabetes, etc). In these rodent disease models, disruption of S1P signalling normalizes myogenic tone and corrects in vivo microvascular dysfunction. Demonstration of S1P signalling and its role as a regulator of myogenic responsiveness in humans is essential in order to evaluate the therapeutic potential for patients. We aim to establish protocols and infrastructure allowing for routine assessment of human resistance arteries and to confirm S1P-dependent microvascular function. Protocols were optimized for perfusion myography-based functional assessment of human resistance arteries isolated from intraoperatively-harvested tissue samples. Mesenteric and skeletal muscle resistance arteries showed intact smooth muscle (dose-dependent vasoconstriction to phenylephrine (logEC50 = 5.9±0.3) and pressure (i.e. myogenic vasoconstriction)) and endothelial function (dilation to acetylcholine (10 μmol/L)). Quantitative RT-PCR and Western blot data show expression of S1P pathway components in human resistance arteries; functional assessment revealed dose-dependent constriction in response to exogenous S1P (logEC50 = 6.8±0.2). Two strategies to increase microvascular S1P levels (i.e. addition of exogenous S1P and inhibition of the cystic fibrosis transmembrane conductance regulator) significantly increased myogenic tone; S1P receptor inhibition decreases myogenic tone at full preservation of phenylephrine-induced vasoconstriction. The present study defines protocols for routine and reliable assessment of human resistance artery function. As a first application, our data confirm a central role for S1P signalling in the regulation of myogenic tone in human resistance arteries, a crucial step towards translation of therapeutic advances in rodent models to the human patient.
- © 2013 by American Heart Association, Inc.