The effects of hemodynamic and interstitial mechanical forces on endothelial biology in vivo have been appreciated for over half a century, regulating vessel network development, homeostatic function, and progression of vascular disease. Investigations using cultures of endothelial cells on two-dimensional (2D) substrates have elucidated important mechanisms by which microenvironmental stresses are sensed and transduced into chemical signaling responses. However recent studies in vivo and in three-dimensional (3D) in vitro models of vascular beds have enabled the investigation of forces and cellular behaviors previously not possible in traditional 2D culture systems. These studies support a developing paradigm that the 3D chemo-mechanical architecture of the vascular niche impacts how endothelial cells both sense and respond to microenvironmental forces. We present evolving concepts in endothelial force sensing and mechanical signaling and highlight recent insights gained from in vivo and 3D in vitro vascular models.
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