Vascular smooth muscle cells (VSMCs) are major contributors to regulation of vascular tone through their contractile flexibility. Along with other stimulus, they are exposed to mechanical cyclic strain. It is thought such stimulus can be a major regulator of phenotypic modulation in smooth muscle cells. Differentiated SMCs are characteristically quiescent and adapt elongated spindle morphology. In this state the cell expresses an extensive range of contractile proteins such as SM α-actin, Smoothelin and Calponin. SMCs in the synthetic end of the phenotype spectrum adapt a rhomboid morphology and display increased growth rate and higher migratory activity. Expression of the contractile proteins are significantly decreased and replaced with organelles involved in protein synthesis. Studies have shown that several non coding micro RNA (miRNA), which negatively regulate gene expression, are differentially expressed in altered SMC phenotypes. However, work into the effect of mechanical stimulus such as shear stress or cyclic strain on miRNA expression is scarce with only a handful so far identified. This study hypothesizes that “cyclic mechanical strain modulates vascular smooth muscle phenotype and ultimately function, mediated by miRNA regulation” This hypothesis was tested by exposing primary derived human aortic smooth muscle cells (HAoSMCs) to cyclic strain in an in vitro model. Results show cyclic strain at 5% and 10% levels of amplitude increases the abundance of contractile phenotype markers. A temporal study of the miRNA profile of SMCs exposed to 10% strain revealed a significant change in expression was evident after 24 hours of strain. Novel chemotaxis experiments demonstrated cyclic strain reduced cell migration, the effect of which was most evident at 24 hours where migration of the cells was less than half that of the static culture. To implicate miRNA as key coordinators in the reduced cell migration observed after cyclic strain, siRNA were targeted against an essential miRNA biogenesis molecule, Argonaute2 (Ago2). Cells transfected with siRNA for Ago2 negated the physiological stimulus of strain and had a marked increase in migration even over the static control. These investigastions highlight the physiological importance of cyclic strain on SMC phenotype and function how the cellular response to this stimulus is orchestrated via miRNA.