Abstract
Plasticity of vascular smooth muscle cells (VSMCs) plays a central role in the onset and progression of proliferative vascular diseases. In adult tissue, VSMCs exist in a physiological contractile-quiescent phenotype, which is defined by lack of the ability of proliferation and migration, while high expression of contractile marker proteins. After injury to the vessel, VSMC shifts from a contractile phenotype to a pathological synthetic phenotype, associated with increased proliferation, migration and matrix secretion. It has been demonstrated that PDGF-BB is a critical mediator of VSMCs phenotypic switch. Atorvastatin calcium, a selective inhibitor of 3-hydroxy-3-methyl-glutaryl l coenzyme A (HMG-CoA) reductase, exhibits various protective effects against VSMCs. In this study, we investigated the effects of atorvastatin calcium on phenotype modulation of PDGF-BB-induced VSMCs and the related intracellular signal transduction pathways. Treatment of VSMCs with atorvastatin calcium showed dose-dependent inhibition of PDGF-BB-induced proliferation. Atorvastatin calcium co-treatment inhibited the phenotype modulation and cytoskeleton rearrangements and improved the expression of contractile phenotype marker proteins such as α-SM actin, SM22α and calponin in comparison with PDGF-BB alone stimulated VSMCs. Although Akt phosphorylation was strongly elicited by PDGF-BB, Akt activation was attenuated when PDGF-BB was co-administrated with atorvastatin calcium. In conclusion, atorvastatin calcium inhibits phenotype modulation of PDGF-BB-induced VSMCs and activation of the Akt signaling pathway, indicating that Akt might play a vital role in the modulation of phenotype.
Highlights
Vascular smooth muscle cells (VSMCs) are highly specialized cells whose principal function is contraction and regulation of blood vessel tone, control of blood pressure and blood flow [1]
The results indicated that atorvastatin calcium had a significant inhibitory effect on Platelet-derived growth factor-BB (PDGF-BB)-induced VSMCs growth in a dose- and time-dependent manner compared to control group
We reported that PDGF-BB increased proliferation and migration, and decreased α-SMA, SM22α and calponin expression of VSMCs, indicating that VSMCs dedifferentiated into proliferative phenotype under stimulation with PDGF-BB
Summary
Vascular smooth muscle cells (VSMCs) are highly specialized cells whose principal function is contraction and regulation of blood vessel tone, control of blood pressure and blood flow [1]. ATV and PDGF-BB-Induced VSMCs exhibit differentiated and contractile phenotype, typically proliferate at an extremely low rate and have a very low synthetic activity. They express a unique repertoire of contractile markers specific to smooth muscle, such as smooth muscle alpha actin (αSMA), SM22α, smooth muscle myosin heavy chain, calponin and alpha-tropomysin[1]. VSMCs can reversibly switch to a dedifferentiated-synthetic state in response to injury such as after angioplasty, stenting, or bypass surgery[4] This phenotypic modulation is characterized by an increased rate of proliferation, migration, and extracellular matrix protein deposition which contributes to intimal hyperplasia[5,6,7]. Much is reported regarding factors and mechanisms that may control VSMCs phenotype modulation, our current knowledge of the mechanisms controlling VSMCs phenotype switching is far from complete
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