Dataset Information

Regulation of vascular smooth muscle cell calcification by syndecan-4/FGF-2/PKC? signalling and cross-talk with TGF?.

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 ?-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-? (TGF?) signalling with SB431542, suggesting cross-talk between FGF-2 and TGF? signalling is crucial for the regulation of VSMC mineralization. Syndecan-4 can also regulate FGF-2 signalling directly via protein kinase C? (PKC?) activation. Biochemical inhibition of PKC? activity using Gö6976, or siRNA-mediated suppression of PKC? expression increases VSMC mineralization; this increase is also prevented with SB431542. Finally, the ability of FGF-2 to inhibit VSMC mineralization is reduced when PKC? 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 TGF? signalling. Our discoveries that FGF-2 and syndecan-4 expression is increased in mineralizing VSMCs and that PKC? regulates FGF-2 and TGF? signalling in VSMCs suggests that the syndecan-4/FGF-2/TGF? signalling axis could represent a new therapeutic target for vascular calcification.

SUBMITTER: Borland SJ

PROVIDER: S-EPMC5852548 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Publications

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

Borland Samantha J SJ Morris Thomas G TG Borland Shona C SC Morgan Mark R MR Francis Sheila E SE Merry Catherine L R CLR Canfield Ann E AE

Cardiovascular research 20171101 13

<h4>Aims</h4>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.<h4>Methods and results</h4>We demonstrate that FGF-2 expression is increased in vascular smooth muscle cells (VSMCs) induced ...[more]

PMID: 29016732

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