Sphingosine-1-Phosphate Signaling Regulates Myogenic Responsiveness in Human Resistance Arteries

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.

Tumor Necrosis Factor/Sphingosine-1-Phosphate Signaling Augments Resistance Artery Myogenic Tone in Diabetes

“…The specimen was immersed in room temperature MOPS-buffered saline, placed on ice, and transported to the laboratory; once the specimen cooled, it was washed with ice-cold MOPS buffer and placed in a Petri dish. Resistance arteries (100-200 mm in diameter) were carefully dissected from the surrounding tissue, with care taken to minimize vessel tension during the isolation process (14).…”

“…Standard procedures were used for resistance artery mRNA isolation, conversion to cDNA, and subsequent quantitative RT-PCR. Specific methodological details have previously been described (14) and are provided in Supplementary Data.…”

Role of age, Rho-kinase 2 expression, and G protein-mediated signaling in the myogenic response in mouse small mesenteric arteries

“…As a third aspect, Izzard and others discuss the issue that myogenic tone can protect vessels from vascular hypertrophy by lowering wall stress, which has been proposed to be the stimulus for hypertrophy (Izzard et al 2005). Recent studies have provided evidence that the G protein-coupled receptor (GPCR) mediated signaling is involved (Schnitzler et al 2008;Schleifenbaum et al 2014;Hui et al 2015;Storch et al 2015;Kauffenstein et al 2016) but mechano-activated ion channels (Welsh et al 2002;Drummond et al 2004;Earley et al 2004;Bulley et al 2012) and interactions between extracellular matrix proteins and membranespanning integrins (Martinez-Lemus et al 2003Jackson et al 2010;Colinas et al 2015) are also thought to contribute to the upstream sensing of pressure in the myogenic response. More detailed knowledge of the signaling pathways in the myogenic response is needed for a more complete understanding of the pathogenesis of hypertension and conditions that entail important risk factors for hypertension, such as: aging, abdominal obesity, diabetes, chronic mental stress, excess salt intake, high cholesterol, lack of physical exercise, or sleep apnea.…”

The sphingosine analog fingolimod (FTY720) enhances tone and contractility of rat gastric fundus smooth muscle

“…Different groups have studied the effects of S1P and FTY720 on the contractility of vascular smooth muscle. [12][13][14][15][16] According to Spijkers et al, FTY720 causes contractions of carotid arteries in spontaneously hypertensive rats that were abolished by endothelium denudation and cyclooxygenase (COX) inhibition. 12 Very little is known about the effects of FTY720 on gastrointestinal smooth muscle.…”