Shear stress: An essential driver of endothelial progenitor cells

The blood flow through vessels produces a tangential, or shear, stress sensed by their innermost layer (i.e., endothelium) and representing a major hemodynamic force. In humans, endothelial repair and blood vessel formation are mainly performed by circulating endothelial progenitor cells (EPCs) characterized by a considerable expression of vascular endothelial growth factor receptor 2 (VEGFR2), CD34, and CD133, pronounced tube formation activity in vitro, and strong reendothelialization or neovascularization capacity in vivo. EPCs have been proposed as a promising agent to induce reendothelialization of injured arteries, neovascularization of ischemic tissues, and endothelialization or vascularization of bioartificial constructs. A number of preconditioning approaches have been suggested to improve the regenerative potential of EPCs, including the use of biophysical stimuli such as shear stress. However, in spite of well-defined influence of shear stress on mature endothelial cells (ECs), articles summarizing how it affects EPCs are lacking. Here we discuss the impact of shear stress on homing, paracrine effects, and differentiation of EPCs. Unidirectional laminar shear stress significantly promotes homing of circulating EPCs to endothelial injury sites, induces anti-thrombotic and anti-atherosclerotic phenotype of EPCs, increases their capability to form capillary-like tubes in vitro, and enhances differentiation of EPCs into mature ECs in a dose-dependent manner. These effects are mediated by VEGFR2, Tie2, Notch, and β1/3 integrin signaling and can be abrogated by means of complementary siRNA/shRNA or selective pharmacological inhibitors of the respective proteins. Although the testing of sheared EPCs for vascular tissue engineering or regenerative medicine applications is still an unaccomplished task, favorable effects of unidirectional laminar shear stress on EPCs suggest its usefulness for their preconditioning.