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Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Arterioscler+Thromb+Vasc+Biol 2015 ; 35 (3): 573-9 Nephropedia Template TP
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Wnt16 Attenuates TGF?-induced Chondrogenic Transformation in Vascular Smooth Muscle #MMPMID25614285
Beazley KE; Nurminsky D; Lima F; Gandhi C; Nurminskaya MV
Arterioscler Thromb Vasc Biol 2015[Mar]; 35 (3): 573-9 PMID25614285show ga
Objective: Phenotypic plasticity of vascular smooth muscle cells (VSMCs) contributes to cardiovascular disease. Chondrocyte-like transformation of VSMCs associates with vascular calcification and underlies the formation of aortic cartilaginous metaplasia induced in mice by genetic loss of matrix Gla protein (MGP). Previous microarray analysis identified a dramatic down-regulation of Wnt16 in calcified MGP-null aortae, suggesting an antagonistic role for Wnt16 in the chondrogenic transformation of VSMCs. Approach and Results: Wnt16 is significantly down-regulated in MGP-null aortae, before the histological appearance of cartilaginous metaplasia, and in primary MGP-null VSMCs. In contrast, intrinsic TGF? is activated in MGP-null VSMCs and is necessary for spontaneous chondrogenesis of these cells in high-density micromass cultures. TGF?3-induced chondrogenic transformation in wild-type VSMCs associates with Smad2/3-dependent Wnt16 down-regulation, but Wnt16 does not suppress TGF?3-induced Smad activation. In addition, TGF?3 inhibits Notch signaling in wild-type VSMCs and this pathway is down-regulated in MGP-null aortae. Exogenous Wnt16 stimulates Notch activity and attenuates TGF?3-induced down-regulation of Notch in wild-type VSMCs, prevents chondrogenesis in MGP-null and TGF?3-treated wild-type VSMCs, and stabilizes expression of contractile markers of differentiated VMSCs. Conclusions: We describe a novel TGF?-Wnt16-Notch signaling conduit in the chondrocyte-like transformation of VSMCs and identify endogenous TGF? activity in MGP-null VSMCs as a critical mediator of chondrogenesis. Our proposed model suggests that the activated TGF? pathway inhibits expression of Wnt16 which is a positive regulator of Notch signaling and a stabilizer of VSMC phenotype. These data advance the comprehensive mechanistic understanding of VSMC transformation and may identify a novel potential therapeutic target in vascular calcification.
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Arterioscler+Thromb+Vasc+Biol 2015 ; 35 (3): 573-9
