Regulation of vascular smooth muscle cell calcification by syndecan-4/FGF-2/PKCα signaling and cross-talk with TGFβ



Borland, SJ, Morris, TG, Borland, SC, Morgan, MR ORCID: 0000-0001-7728-9883, Francis, SE, Merry, CLR and Canfield, AE
(2017) Regulation of vascular smooth muscle cell calcification by syndecan-4/FGF-2/PKCα signaling and cross-talk with TGFβ. Cardiovascular Research, 113 (13). pp. 1639-1652.

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Abstract

Aims Vascular calcification is a major cause of morbidity and mortality. Fibroblast growth factor-2 (FGF-2) plays an instructive role in osteogenesis and bone development, but its role in vascular calcification was unknown. Therefore, we investigated the involvement of FGF-2 in vascular calcification and determined the mechanism by which it regulates this process. Methods and results We demonstrate that FGF-2 expression is increased in vascular smooth muscle cells (VSMCs) induced to deposit a mineralized matrix by incubation with β-glycerophosphate. FGF-2 is also localized to sites of calcification within human atherosclerotic plaques. The expression of syndecan-4, a heparan sulfate proteoglycan which regulates FGF-2 signalling, is also increased in mineralizing VSMCs and co-localizes with FGF-2 in human calcified atherosclerotic plaques. Exogenous FGF-2 inhibits VSMC mineralization, and this inhibition is reduced when syndecan-4 expression is knocked-down using siRNA. Biochemical inhibition of FGFR signalling using a pan FGFR inhibitor (BGJ398) or knocking-down syndecan-4 expression in VSMCs using siRNA increases VSMC mineralization. These increases are prevented by inhibiting transforming growth factor-β (TGFβ) signalling with SB431542, suggesting cross-talk between FGF-2 and TGFβ signalling is crucial for the regulation of VSMC mineralization. Syndecan-4 can also regulate FGF-2 signalling directly via protein kinase Cα (PKCα) activation. Biochemical inhibition of PKCα activity using Gö6976, or siRNA-mediated suppression of PKCα expression increases VSMC mineralization; this increase is also prevented with SB431542. Finally, the ability of FGF-2 to inhibit VSMC mineralization is reduced when PKCα expression is knocked-down. Conclusion This is the first demonstration that syndecan-4 promotes FGF-2 signalling, and in turn, suppresses VSMC mineralization by down-regulating TGFβ signalling. Our discoveries that FGF-2 and syndecan-4 expression is increased in mineralizing VSMCs and that PKCα regulates FGF-2 and TGFβ signalling in VSMCs suggests that the syndecan-4/FGF-2/TGFβ signalling axis could represent a new therapeutic target for vascular calcification.

Item Type: Article
Uncontrolled Keywords: vascular smooth muscle cells, vascular calcification, syndecan-4, fibroblast growth factor-2, Transforming growth factor-β
Depositing User: Symplectic Admin
Date Deposited: 25 Jul 2017 11:41
Last Modified: 19 Jan 2023 06:58
DOI: 10.1093/cvr/cvx178
Open Access URL: https://academic.oup.com/cardiovascres/article/410...
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3008610