Mechanical forces and metabolic changes cooperate to drive cellular memory and endothelial phenotypes.

Endothelial cells line the innermost layer of arterial, venous, and lymphatic vascular tree and accordingly are subject to hemodynamic, stretch, and stiffness mechanical forces. Normally quiescent, endothelial cells have a hemodynamic set point and become "activated" in response to disturbed hemodynamics, which may signal impending nutrient or gas depletion. Endothelial cells in the majority of tissue beds are normally inactivated and maintain vessel barrier functions, are anti-inflammatory, anti-coagulant, and anti-thrombotic. However, under aberrant mechanical forces, endothelial signaling transforms in response, resulting cellular changes that herald pathological diseases. Endothelial cell metabolism is now recognized as the primary intermediate pathway that undergirds cellular transformation. In this review, we discuss the various mechanical forces endothelial cells sense in the large vessels, microvasculature, and lymphatics, and how changes in environmental mechanical forces result in changes in metabolism, which ultimately influence cell physiology, cellular memory, and ultimately disease initiation and progression.