Arteriogenesis is an important adaptive remodeling process which involves the enlargement and thickening of arterioles running in parallel to an occluded artery, and is capable of partially compensating the consequences of peripheral artery disease by creating natural bypasses. The arteriolar remodeling is orchestrated by changes in the biomechanical forces to which the vessel wall is exposed to. Based on Poiseuille’s equation, progressive stenosis of the main artery will lead to an increase in resistance hence to a significant drop in pressure distal to the site of occlusion. As a consequence, the pressure difference between both ends of the collateral arterioles is enhanced resulting in an increased flow and, as a consequence, an increase in shear stress. Laminar shear stress is thought to be responsible for the initial dilation of the collateral arterioles through activation of endothelial cell nitric oxide synthase. Moreover, the NO-mediated dilation decreases the wall thickness and thus – according to the Laplace equation – results in an increase in circumferential wall stress. While the impact of shear stress on collateral growth has been extensively studied, the role of circumferential wall stress in the early phase of arteriogenesis is less well defined. To this end, our studies indicate that wall stress or biomechanical stretch activates the transcription factor AP-1 in endothelial and smooth muscle cells and controls the expression of MCP-1 – an important determinant of arteriogenesis. Furthermore, this biomechnical force promotes the activation of smooth muscle cells by imparing the function of myocardin – a crucial regulator of the contractile capacity of these cells – and acts in concert with shear stress to reprogram G-protein signaling cascades in smooth muscle cells. Collectively, our findings suggest that biomechanical stress controls rate-limiting mechanisms during the remodeling of collateral arterioles and contributes to a mechanosensitive gene expression in vascular smooth muscle cells during arteriogenesis.