Feedback between mechanosensitive signaling and active forces governs endothelial junction integrity

Abstract

The formation and recovery of gaps in the vascular endothelium governs a wide range of physiological and pathological phenomena, from angiogenesis to tumor cell extravasation. However, the interplay between the mechanical and signaling processes that drive dynamic behavior in vascular endothelial cells is not well understood. In this study, we propose a chemo-mechanical model to investigate the regulation of endothelial junctions as dependent on the feedback between actomyosin contractility, VE-cadherin bond turnover, and actin polymerization, which mediate the forces exerted on the cell-cell interface. Simulations reveal that active cell tension can stabilize cadherin bonds, but excessive RhoA signaling can drive bond dissociation and junction failure. While actin polymerization aids gap closure, high levels of Rac1 can induce junction weakening. Combining the modeling framework with experiments, our model predicts the influence of pharmacological treatments on the junction state and identifies that a critical balance between RhoA and Rac1 expression is required to maintain junction stability. Our proposed framework can help guide the development of therapeutics that target the Rho family of GTPases and downstream active mechanical processes.

Inflammation modulates intercellular adhesion and mechanotransduction in human epidermis via ROCK2

“…The actin-myosin tension has a dual role in regulating epithelial and endothelial cell-cell contact, either stabilizing AJ structure or driving its disassembly, 81 which also depends on the alignment and dynamics of AJ-associated cytoskeletal structures. For example, the rearrangement of linear perijunctional actomyosin belt into radial stress fibers represents a hallmark of AJ disassembly and reduced barrier function.…”

Active viscoelastic models for cell and tissue mechanics

“…In other words, based on the research question, the phenomenon of interest, length and time scales and characteristics of the relevant microstructures can be incorporated into biophysical models. For example, at the molecular scale, chemomechanical [103,116] and molecular clutch models [117][118][119] are used to study cell-cell and cell-ECM adhesions, at the cell-scale statistical approaches can be employed to study cell mechanics [120][121][122], and cellular Potts (CPM) [123][124][125], vertex [126,127] and self-propelled Voronoi [128][129][130] models are introduced to study the mechanical behaviour of epithelial monolayers in two dimensions and three dimensions. The level of detail can be further reduced by describing the outcomes of experiments using phenomenological models before examining the underlying mechanisms.…”

Emergent mechanical control of vascular morphogenesis

“…Embryos were then washed in PBSMT five times for 1 hour, followed by two washes for 1 hour each in 0.1% Triton X-100 in PBS at 4°C on a rocking platform protected from light. Embryos were then incubated with increasing glycerol concentrations for 30 min each (10,20,40, and 60% glycerol in PBS) and lastly stored protected from light in 80% glycerol in PBS at 4°C until imaging on a Zeiss 780 confocal microscope using a glass bottomed cell culture plate (MatTek; Fig. 5D and fig.…”

“…For example, fluid shear stress (10,11), substrate stiffness (12)(13)(14), and forces (15)(16)(17)(18) regulate angiogenesis, vasculogenesis, and vascular pathologies. The cell adhesion molecule platelet EC adhesion molecule-1 (PECAM1)/CD31 interacts with VEGFR2 to sense alterations in fluid flow and modulates the function of CDH5/VE-cadherin and, hence, endothelial cell-cell junctions (19)(20)(21). In addition, ECs are highly sensitive to cell matrix adhesions (22).…”