P4.32: Inactivation of Serum Response Factor Contributes to Decrease Vascular Muscular Tone and Arterial Stiffness in Mice

• Published in: Artery research Vol. 7; no. 3-4; p. 144
• Main Authors: Galmiche, G., Regnault, V., Li, Z., Lacolley, P.
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 2013; Springer Nature B.V; BMC
• Subjects: Conference Abstract; Genes; Kinases; Phosphatase; Smooth muscle; Veins & arteries
• ISSN: 1872-9312; 1876-4401; 1876-4401
• DOI: 10.1016/j.artres.2013.10.150

Rationale Vascular smooth muscle cell (VSMC) phenotypic modulation plays an important role in arterial stiffening associated with ageing. Serum response factor (SRF) is a major transcription factor regulating smooth muscle (SM) genes involved in maintenance of the contractile state of VSMCs. Objective We investigated whether SRF and its target genes regulate intrinsic SM-tone and thereby arterial stiffness. Methods and results The SRF gene was inactivated (SRF SMKO ) specifically in VSMCs by injection of tamoxifen into adult transgenic mice. Fifteen days later, arterial pressure and carotid thickness were lower in SRF SMKO than in control mice. The carotid distensibility/pressure and elastic modulus/wall stress curves showed a greater arterial elasticity in SRF SMKO without modification in collagen/elastin ratio. In SRF SMKO , vasodilation was decreased in aorta and carotid arteries whereas a decrease in contractile response was found in mesenteric arteries. By contrast, in mice with inducible SRF over-expression, the in vitro contractile response was significantly increased in all arteries. Without endothelium, the contraction was reduced in SRF SMKO compared with control aortic rings due to impairment of the NO pathway. Contractile components (SM-actin and myosin light chain), regulators of the contractile response (myosin light chain kinase, myosin phosphatase target subunit 1 and protein kinase C-potentiated myosin phosphatase inhibitor) and integrins were reduced in SRF SMKO . Conclusion SRF controls vasoconstriction in mesenteric arteries via VSMC phenotypic modulation linked to changes in contractile protein gene expression. SRF-related decreases in vasomotor tone and cell-matrix attachment increase arterial elasticity in large arteries.