Pericyte actomyosin-mediated contraction at the cell–material interface can modulate themicrovascular niche

Abstract

Pericytes physically surround the capillary endothelium, contacting and communicatingwith associated vascular endothelial cells via cell–cell and cell–matrix contacts.Pericyte–endothelial cell interactions thus have the potential to modulate growth andfunction of the microvasculature. Here we employ the experimental finding that pericytescan buckle a freestanding, underlying membrane via actin-mediated contraction. Pericyteswere cultured on deformable silicone substrata, and pericyte-generated wrinkles wereimaged via both optical and atomic force microscopy (AFM). The local stiffness ofsubcellular domains both near and far from these wrinkles was investigated by usingAFM-enabled nanoindentation to quantify effective elastic moduli. Substratum bucklingcontraction was quantified by the normalized change in length of initially flat regionsof the substrata (corresponding to wrinkle contour lengths), and a model wasused to relate local strain energies to pericyte contractile forces. The nature ofpericyte-generated wrinkling and contractile protein-generated force transduction wasfurther explored by the addition of pharmacological cytoskeletal inhibitors thataffected contractile forces and the effective elastic moduli of pericyte domains.Actin-mediated forces are sufficient for pericytes to exert an average bucklingcontraction of 38% on the elastomeric substrata employed in these in vitro studies.Actomyosin-mediated contractile forces also act in vivo on the compliant environment of themicrovasculature, including the basement membrane and other cells. Pericyte-generatedsubstratum deformation can thus serve as a direct mechanical stimulus to adjacentvascular endothelial cells, and potentially alter the effective mechanical stiffness ofnonlinear elastic extracellular matrices, to modulate pericyte–endothelial cellinteractions that directly influence both physiologic and pathologic angiogenesis.