Vascular endothelial integration of multiple biophysical stimuli

By virtue of their anatomical position at the interface between the bloodstream and the blood vessel wall, vascular endothelial cells (ECs) in vivo are constantly subjected to a complex and highly dynamic combination of biophysical stimuli. These stimuli, which include fluid shear stress, pressure, stretch forces, curvature effects, and contact stresses due to substrate topography and rigidity, fundamentally shape EC structure and function. Numerous studies have focused on the response of ECs to single stimuli in vitro. For instance, EC responses to flow have been investigated since the 1980s. More recently, the impact of the physical properties of the subendothelial basement membrane including topography and rigidity has also received some attention. However, research on how ECs integrate multiple biophysical stimuli and the mechanisms underlying this integration remains very limited. In this perspective article, we briefly review what is known about EC responses to multiple synergistic or antagonistic stimuli, and we subsequently present a framework for how an EC may integrate and interpret two physical stimuli to which it is simultaneously subjected. Such a framework promises to advance our understanding of EC integration of multiple biophysical cues which is essential for elucidating the role of endothelial mechanobiology in regulating vascular health and disease.