Integration of basal topographic cues and apical shear stress in vascular endothelial cells

Abstract

In vivo, vascular endothelial cells (VECs) are anchored to the underlying stroma through a specialization of the extracellular matrix, the basement membrane (BM) which provides a variety of substratum associated biophysical cues that have been shown to regulate fundamental VEC behaviors. VEC function and homeostasis are also influenced by hemodynamic cues applied to their apical surface. How the combination of these biophysical cues impacts fundamental VEC behavior remains poorly studied. In the present study, we investigated the impact of providing biophysical cues simultaneously to the basal and apical surfaces of human aortic endothelial cells (HAECs). Anisotropically ordered patterned surfaces of alternating ridges and grooves and isotropic holed surfaces of varying pitch (pitch = ridge or hole width + intervening groove or planar regions) were fabricated and seeded with HAECs. The cells were then subjected to a steady shear stress of 20 dyne/cm2 applied either parallel or perpendicular to the direction of the ridge/groove topography. HAECs subjected to flow parallel to the ridge/groove topography exhibited protagonistic effects of the two stimuli on cellular orientation and elongation. In contrast, flow perpendicular to the substrate topography resulted in largely antagonistic effects. Interestingly, the behavior depended on the shape and size of the topographic features. HAECs exhibited a response that was less influenced by the substratum and primarily driven by flow on isotropically ordered holed surfaces of identical pitch to the anistropically ordered surfaces of alternating ridges and grooves. Simultaneous presentation of biophysical cues to the basal and apical aspects of cells also influenced nuclear orientation and elongation; however, the extent of nuclear realignment was more modest in comparison to cellular realignment regardless of the surface order of topographic features. Flow-induced HAEC migration was also influenced by the ridge/groove surface topographic features with significantly altered migration direction and increased migration tortuosity when flow was oriented perpendicular to the topography; this effect was also pitch-dependent. The present findings provide valuable insight into the interaction of biologically relevant apical and basal biophysical cues in regulating cellular behavior and promise to inform improved prosthetic design.

Accelerated endothelial wound healing on microstructured substrates under flow

“…Among these, flow-mediated endothelial Wall Shear Stress (WSS) and substrate topography are known to play a critical role in the control of vascular permeability in vivo. Previous studies reported on the combined effect of substrate topography and flow either on single cell migration or on the morphology of confluent monolayers [21][22]. However, their combined contribution to wound healing, although likely to be important, has never been addressed.…”

Regeneration of the Vascular System

“…One example is the effect of oxygen gradient, which induces SMC migration and ECM remodeling that is important to achieve a functional blood vessel [132]. In this section, we will mostly focus on the mechanical conditions that blood vessels face, but many of the other factors have also been experimented with, and there is room for more in depth understanding of the effects of all of these different factors and their interplay, such as in the case of basal topographic features and shear stress combined effect on endothelial cells [133].…”

Influence of Extracellular Matrix Proteins and Substratum Topography on Corneal Epithelial Cell Alignment and Migration

“…The modulation of cellular behavior and differentiation by soluble factors, 15,[36][37][38][39] surface chemistry, [40][41][42][43][44] and biophysical attributes of the extracellular microenvironment [45][46][47][48] has been well established. While, the majority of studies have investigated only one type of biophysical or chemical cue in isolation, a limited number have explored the interaction between multiple biophysical cues, 11,49 surface chemistry, 19,50 or soluble cytoactive factors. 15 Here we have demonstrated that the simultaneous presentation of substratum topographic cues and surfaceassociated biochemical cues potently modulated cellular behavior.…”

“…Vascular endothelial cells have been documented to integrate the simultaneous presentation of multiple biophysical cues (substratum topography and apical shear stress). 11 Importantly, biophysical cues have been demonstrated to also modulate the response of cells to soluble cytoactive factors 12 as well as to therapuetic agents. 13,14 Additionally, the soluble culture environment can alter the response of cells to biophysical cues.…”