Abstract 185: The Impact of Cyclic Strain on Focal Adhesion Signaling and miRNA Profile in Vascular Smooth Muscle Cells

Abstract

Vascular smooth muscle cells (VSCM) are major contributors to the regulation of vascular tone through their contractile flexibility. Along with other stimulus, they are exposed to mechanical cyclic strain. This is induced by changes in arterial blood pressure waveforms, generated from the left ventricle. It is thought such stimulus can be a major regulator of phenotypic modulation in smooth muscle cells. These altered states of VSMC fate can have a direct influence on cell function, including proliferation, apoptosis, migration and adhesion. This is considered to play a critical role in the pathogenesis of cardiovascular disease. We have shown that cyclic strain, an important physiological stimulus, has a compounding influence on smooth muscle cell function via mechanotransduction. Increased strain has shown to increase SMC adhesion, proliferation and migration. We hypothesise that the effect of mechanical cyclic strain is transduced through the cell via integrin rich focal adhesions, which can alter the miRNA signature of vascular smooth muscle cells and ultimately play a pivotal role in cell function. The Focal Adhesion Kinase (FAK) protein and its endogenous negative regulator FAK Related Non Kinase (FRNK) are known to play a commanding role in integrin signaling. We propose that down regulation of FAK by either siRNA technology or over expression of FRNK will negate the effect of pathological mechanical strain on cell function. We also predict regulation of expression on individual miRNA, through use of Pre-Mir and Anti-Mir technology could yield a similar effect. In the current study we exposed primary derived human aortic smooth muscle cells, in an in vitro model, to cyclic strain to assess its influence on focal adhesions, integrin and miRNA expression. We have concluded thus far that increased cyclic strain shows increased cell migration, adhesion and proliferation. It also alters the miRNA signature as we have shown with a panel of mechano-sensitive miRNA. Coinciding with this we have also demonstrated the impact on cellular function from knockdown of miRNA biogenesis molecules such as Drosha, Dicer, Exportin 5 and Argonaute2 through use of siRNA.