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1 Vascular Health Research Centre, Dublin City University, Dublin, Leinster, Ireland
2 Department of Surgery, University of Rochester, Rochester, NY, USA
* To whom correspondence should be addressed. E-mail: paul.cahill{at}dcu.ie.
Vascular smooth muscle cell (SMC) phenotypic modulation is a key factor in vascular pathology. We investigated the role of Notch receptor signaling in controlling human vascular smooth muscle cell (HuSMC) differentiation in vitro, and established a role for cyclic strain-induced changes in Notch signaling in promoting this phenotypic response. The expression of 
-actin, calponin, myosin and smoothelin was examined by immunocytochemistry, Western blot analysis and quantitative real time PCR in HuSMC cultured under static conditions following forced over-expression of constitutively active Notch 1 and 3 receptors, inhibition of endogenous CBF-1/RBP-Jk signaling and following exposure to cyclic strain using a Flexercell Tension Plus Unit. Over-expression of constitutively active Notch intracellular receptors (Notch 1 IC and 3 IC) resulted in a significant down-regulation of -actin, calponin, myosin and smoothelin expression, an effect that was significantly attenuated following inhibition of Notch mediated CBF-1/RBP-Jk dependent signaling by co-expression of RPMS-I and by selective knockdown of bHLH factors (Hrt-1, 2 and 3) using targeted siRNA. Cells cultured under conditions of defined equibiaxial cyclic strain (10% strain, 60 cycles/min, 24 h) exhibited a significant reduction in Notch 1 and 3 IC expression, concomitant with a significant increase in SMC differentiation marker expression. Moreover, this cyclic strain-induced increase was further enhanced following inhibition of CBF-1/RBP-Jk dependent-signaling with RPMS-1. These findings suggest that Notch promotes changes in HuSMC phenotype via activation of CBF-1/RBP-Jk dependent pathways in vitro and contributes to the phenotypic response of SMC to cyclic strain-induced changes in SMC differentiation.
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