Mechanical Stretch Increases MMP-2 Production in Vascular Smooth Muscle Cells via Activation of PDGFR-β/Akt Signaling Pathway

Abstract

Increased blood pressure, leading to mechanical stress on vascular smooth muscle cells (VSMC), is a known risk factor for vascular remodeling via increased activity of matrix metalloproteinase (MMP) within the vascular wall. This study aimed to identify cell surface mechanoreceptors and intracellular signaling pathways that influence VSMC to produce MMP in response to mechanical stretch (MS). When VSMC was stimulated with MS (0–10% strain, 60 cycles/min), both production and gelatinolytic activity of MMP-2, but not MMP-9, were increased in a force-dependent manner. MS-enhanced MMP-2 expression and activity were inhibited by molecular inhibition of Akt using Akt siRNA as well as by PI3K/Akt inhibitors, LY293002 and AI, but not by MAPK inhibitors such as PD98059, SP600125 and SB203580. MS also increased Akt phosphorylation in VSMC, which was attenuated by AG1295, a PDGF receptor (PDGFR) inhibitor, but not by inhibitors for other receptor tyrosine kinase including EGF, IGF, and FGF receptors. Although MS activated PDGFR-α as well as PDGFR-β in VSMC, MS-induced Akt phosphorylation was inhibited by molecular deletion of PDGFR-β using siRNA, but not by inhibition of PDGFR-α. Collectively, our data indicate that MS induces MMP-2 production in VSMC via activation of Akt pathway, that is mediated by activation of PDGFR-β signaling pathways.

Mechanical stretch enhances the expression and activity of osteopontin and MMP-2 via the Akt1/AP-1 pathways in VSMC

“…Therefore, we hypothesized that OPN produced in VSMC exposed to MS might regulate MMP production in vasculature. Consistent with the findings of our previous study, in which MS increased MMP-2, but not MMP-9 production in VSMC [36], the present study also showed mice were treated with Ang II or L-LAME for 13 days to increase blood pressure, and then aorta was isolated to determine MMP-2 production. Immunohistochemical stain of MMP-2 in the aorta of Ang II-induced hypertensive mice (A) or L-NAME-induced hypertensive mice (B) was compared with that of control mice (Veh).…”

Altered matrix metalloproteinase-2 and -9 expression/activity links placental ischemia and anti-angiogenic sFlt-1 to uteroplacental and vascular remodeling and collagen deposition in hypertensive pregnancy

“…These findings are consistent with previous reports [22] and support a role of MMPs in the uteroplacental and vascular remodeling associated with Norm-Preg. Importantly, MMPs immunostaining was particularly apparent in the aortic media, consistent with reports that vascular smooth muscle cells (VSMCs) are a major source of MMPs [36, 37]. …”

Matrix Metalloproteinase 2 as a Potential Mediator of Vascular Smooth Muscle Cell Migration and Chronic Vascular Remodeling in Hypertension

“…Arteries submitted to increased transmural pressure showed increased MMP-2 activity and elastin proteolysis [32]. Mechanical stress increased MMP-2 in VSMCs by activating the platelet-derived growth factor mechanoreceptor (PDGF-R) and protein kinase B/Akt signaling pathways [34] (fig. 1b).…”