Inactivation of Serum Response Factor Contributes To Decrease Vascular Muscular Tone and Arterial Stiffness in Mice

Abstract

Rationale: Vascular smooth muscle (SM) cell phenotypic modulation plays an important role in arterial stiffening associated with aging. Serum response factor (SRF) is a major transcription factor regulating SM genes involved in maintenance of the contractile state of vascular SM cells. 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 SM-specific knockout of SRF (SRF SMKO ) specifically in vascular SM cells 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 overexpression, 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 owing 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 . Conclusions: SRF controls vasoconstriction in mesenteric arteries via vascular SM cell 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.

The Structural Factor of Hypertension

“…The role played by increased VSMC tone has been suggested from gene expression profile studies, 92 theoretical model of 3 dimensional arterial mechanics, 93 and atomic force microscopy 94 and demonstrated in knockout mice with deletion of the VSMC serum response factor, a major transcription factor regulating smooth muscle genes involved in maintenance of the contractile state. 95 Altogether, these results suggest that not only the organization and content of the ECM but also the changes in the structural and functional properties of the VSMCs can influence arterial stiffness.…”

Matrix Metalloproteinases Promote Arterial Remodeling in Aging, Hypertension, and Atherosclerosis

“…Proinflammation is not instigated by “professional” immunological cells such as leukocytes, but rather by phenotypically shifted arterial wall cells, including ECs, VSMCs, and fibroblasts (for reviews) (Figure) 1, 2 . Proinflammation-associated arterial stiffening and BP increase are mainly determined by VSMC phenotypic shift or ECM modifications, or their combination 34 . Intrinsic stiffening of VSMCs increases with age, which is likely linked to activity of serum response factor (SRF) 34, 35 .…”

“…Proinflammation-associated arterial stiffening and BP increase are mainly determined by VSMC phenotypic shift or ECM modifications, or their combination 34 . Intrinsic stiffening of VSMCs increases with age, which is likely linked to activity of serum response factor (SRF) 34, 35 . SRF gene inactivation reduces vasoconstriction and increases intrinsic elasticity in the carotid artery in the absence of a significant change in ECM 34 .…”

“…Intrinsic stiffening of VSMCs increases with age, which is likely linked to activity of serum response factor (SRF) 34, 35 . SRF gene inactivation reduces vasoconstriction and increases intrinsic elasticity in the carotid artery in the absence of a significant change in ECM 34 . Alteration of arterial stiffness in SRF-invalidated mice results from the downregulation of contractile protein genes, cytoskeletal organization, and in cell-matrix interactions 34 .…”

Circulation Research “In This Issue” Anthology

“…VSMC Phenotype Modulation and Arterial Stiffness (p 1035) 21 To avoid age-related cardiovascular problems, vascular smooth muscle cells need to stay relaxed say Galmiche et al…”