Differential role for stromal interacting molecule 1 in the regulation of vascular function.

We determined the in vivo role of stromal-interacting molecule 1 (STIM1) in the regulation of vascular function using endothelial cell (EC)- and smooth-muscle (SM)-specific knockout mice. Systolic blood pressure and glucose levels were similar in all mice (Stim1(SMC-/-), Stim1(SMC-/+), Stim1(EC-/-), Stim1(EC-/+)), but body weight was reduced in Stim1(EC-/-) and Stim1(SMC-/-) mice. The contraction of arteries in response to phenylephrine was significantly reduced in Stim1(SMC-/-) mice only. However, contraction to thromboxane and KCl was similar in all groups. The endothelium-dependent relaxation (EDR) was impaired in Stim1(EC-/+) and drastically reduced in Stim1(EC-/-) mice while the endothelium-independent vasorelaxation was similar among all groups. Acute downregulation of STIM1 in arteries reduced EDR and the contractile response to phenylephrine, while the contractile response to thromboxane was not affected. NADPH oxidase activity was increased only in Stim1(EC-/+) and Stim1(EC-/-) mice. Calcium (Ca(2+)) entry in endothelial cells stimulated with thrombin and histamine had the pharmacological features of store-operated Ca(2+) entry (SOCE) and was dependent on STIM1 expression. We conclude that STIM1 plays opposing roles in vascular smooth muscle vs. endothelial cells in the regulation of vascular reactivity.

Inactivation of serum response factor contributes to decrease vascular muscular tone and arterial stiffness in mice.

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.