Forces and mechanotransduction in 3D vascular biology

Abstract

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.

Figure 1

A) Force diagram of a microvessel under flow. Hemodynamic flow (gray arrows) exerts frictional shear stress σ_ss parallel to the vessel wall, and pressure P_ves normal to the vessel wall. At the basal interface, cell-ECM stresses σ_ecm are driven by integrin ligation to basement membrane and interstitial ECMs. Interstitial fluid accumulation increases interstitial pressures P_int that act on the outer vessel membrane. Transmural pressure P_TM is defined by the difference vessel and interstitial pressures. B) Representative diagram of the intracellular localization of mechanosensors and transducers during endothelial exposure to flow, noting how individual elements are integrated in a force-sensitive continuum. Adapted from [6]. C) (top) Timelapse images of sprouting angiogenesis (white arrows) and anastomosis events (blue arrows) in E8.5 yolk sacs from [64]. (bottom) Timelapse images of flow-driven vessel arterial fusion events in yolk sacs from [47]. D) Using 3D in vitro vessel models, a shear stress threshold was identified for both luminal (left) and transmural (right) flows that drives vascular sprouting. Scale bars 50 and 100 microns. [3].