Frequency-Dependent Phenotype Modulation of Vascular Smooth Muscle Cells under Cyclic Mechanical Strain

Abstract

Phenotype transformation of vascular smooth muscle cells (VSMCs) is known to be modulated by mechanical strain. The present study was designed to investigate how different frequencies of mechanical strain affected VSMC phenotype. VSMCs were subjected to the strains of 10% elongation at 0, 0.5, 1 and 2 Hz for 24 h using a Flexercell strain unit. VSMC phenotype was assessed by cell morphology, measurement of two-dimensional cell area, Western blotting for protein and RT-PCR for mRNA expression of differentiation markers. Possible protein kinases involved were evaluated by Western blotting with their specific antibodies. The strains at certain frequencies could induce a contractile morphology in VSMC with almost perpendicular alignment to the strain direction. The strains also regulated protein and mRNA expression of several differentiation markers, as well as the activation of extracellular signal-regulated kinases (ERKs), p38 MAP kinase and protein kinase B (Akt) in a frequency-dependent manner. Furthermore, the inhibition of the p38 pathway could block the frequency-induced phenotype modulation of VSMCs, but not inhibition of ERK or Akt pathways. These results indicate that the frequency of cyclic strain can result in the differentiated phenotype of VSMCs, and it is mediated at least partly by the activation of the p38 pathway.

The early- and late stages in phenotypic modulation of vascular smooth muscle cells: Differential roles for lysophosphatidic acid

“…To answer these questions and reconcile the paradoxical findings with those reports demonstrating that activation of the ERK and p38 MAPK pathways induces PM [40][41][42][43] and that stretch increases ERK and p38 MAPK activity while maintaining the differentiated phenotype [16,17], we hypothesized that there may exist an early PM of dissociated VSMC that occurs within hours after the removal of the physiological cues acting on the vessel wall, which may have escaped detection. In addition, we posited that early PM has a different molecular mechanism from that of late PM, in which activation of ERK and p38 MAPK pathways is important.…”

“…While endothelial cells are primarily subjected to the shear stress resulting from blood flow, VSMC are primarily subjected to the stretch resulting from blood pressure. When VSMC are dissociated, they become deprived of the mechanical stimuli, which have been proved by numerous studies [12][13][14][15][16][17][18][19][20][21] to play a role in PM. Second, if inhibition of ERK and the p38 MAPK pathways is a prerequisite for maintaining the differentiated phenotype [40][41][42][43], how can one explain the findings that stretch not only increased ERK and p38 MAPK activity [44][45][46], but also at the same time was sufficient for maintaining the differentiated phenotype [16,17]?…”

“…Mechanical factors, soluble biochemical factors, and extracellular matrix components have been proved to induce PM. Studies with cultured cells [12][13][14][15][16][17] and with intact cultured vessels [18][19][20][21] have shown that mechanical stimulation is able to maintain VSMC in the differentiated phenotype, typified by a high level of SMC-specific marker genes or a low proliferation rate. Soluble biochemical factors, including platelet-derived growth factor (PDGF) [22][23][24][25], transforming growth factor (TGF)-β [26,27], and retinoic acid [28][29][30][31] have been shown to affect PM.…”

The effect of mechanical strain on soft (cardiovascular) and hard (bone) tissues

“…The induction of smooth muscle α-actin is mediate by activation of JNK and p38 MAPK pathway. 57 Thus mechanical strain leads to migration, proliferation and contraction. The primary genes encoding SMC contractile proteins are regulated by Cell Adhesion & Migration volume 7 issue 2 as small GTP-binding proteins Rho, Rac and Cdc42.…”

Atheromas Feel the Pressure

“…Transmission of these forces, particularly cyclic strain, in the context of the local environment produces a distinct set of responses in VSMCs, including altered cytoskeletal arrangement, 36,37 changes in VSMC proliferation, 38,39 apoptosis, 2,40 -42 and phenotype 43,44 ; most of these responses are determined by altered gene expression. VSMCs modulate an array of genes in atherosclerosis, but only in the presence of the unique plaque microenvironment.…”