J027 Serum response factor involvement in myogenic tone regulation in resistance arteries - 17/04/09
Résumé |
Serum Response Factor (SRF) has emerged as a dispensable transcription factor for cellular growth but an absolutely essential orchestrator of actin cytoskeleton and contractile homeostasis. SRF is a founding member of MADS domain-containing family of transcription factors and is present in most, if not all, species from animals to plants and fungus kingdoms. Signaling to SRF occurs principally through mitogen-activated protein kinase (MAPK) or RhoA pathways that converge on the nucleus to stimulate gene expression. In the microcirculation, diameter adjustments in response to change in intraluminal pressure or flow mainly depend on the integrity of the vascular cytoskeleton. We thus hypothesised that the deletion in SRF will affect the mechanotransduction in resistance arteries. To address the role of SRF, the tail caudal and mesenteric arteries from inducible SRF KO mice and their littermate control were mounted in an arteriograph. Contraction to stepwise increase in pressure (myogenic tone) and relaxation to progressive increases in intraluminal flow were determined in each group. The protein and gene expressions were quantificated by western blot and qPCR. SRF deficiency reduced myogenic tone in tail arteries (CT:16.3±3.2 % of Passive Diameter (PD) versus KO:5.9±2.3 % PD; P<0.05) and in mesenteric arteries (CT:26±2.3 % PD versus KO:11±1.8 % PD; P<0.05). No effect was observed on the flow mediated dilation and receptor dependant contraction induced by Phenylephrine, Angiotensine II and U46619. SRF alteration induced modifications of contraction signalling pathways as p38 MAP kinase, Myosin Light Chain Kinase, Myosin Light Chain, Src, Caveolin 1 or cytoskeleton proteins. Furthermore, actin polymerisation was also spoiled. This study reported for the first time that the SRF inhibition with an inducible KO significantly affected specifically the myogenic tone. This suggests that SRF is involved in the pressure mechanotransduction in resistance arteries. Due to the central role of myogenic tone in vascular disorders and organs autoregulation this finding opens new perspectives in the pathophysiology of the microcirculation and provides new therapeutic targets.
Le texte complet de cet article est disponible en PDF.Vol 102 - N° S1
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