Endothelial cells as mechanical transducers: enzymatic activity and network formation under cyclic strain.

Although it is established that endothelial cells can respond to external mechanical cues (e.g., alignment in the direction of fluid shear stress), the extent to which mechanical stress and strain applied via the endothelial cell substrate impact biomolecular and cellular processes is not well-understood. This issue is particularly important in the context of inflammation, vascular remodeling, and cancer progression, as each of these processes occurs concurrently with localized increases in strain and marked changes in molecules secreted by adjacent cells. Here, we systematically vary the level and duration of cyclic tensile strain applied to human dermal microvascular and bovine capillary endothelial cells via substrate deflection, and then correlate these cues with the secretion of extracellular matrix-degrading enzymes and a morphological transition from confluent monolayers to well-defined multicellular networks that resemble capillary tube-like structures. For a constant chemical environment, we find that super-physiological mechanical strain stimulates both endothelial cell secretion of latent matrix metalloprotease-2 and multicellular networks in a time- and strain-dependent manner. These results demonstrate coupling between the mechanical and biochemical states of microvascular endothelial cells, and indicate that elevated local stress may directly impact new capillary growth (angiogenesis) toward growing tumors and at capillary wall defect sites.