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Free keywords:
Actin Cytoskeleton/*metabolism
*Actomyosin/metabolism
Adherens Junctions/physiology
Antigens, CD/genetics/*metabolism
Biomechanical Phenomena
Cadherins/genetics/*metabolism
Calcimycin/pharmacology
Calcium Ionophores/pharmacology
*Calcium Signaling/drug effects
Cytochalasin D/pharmacology
Filamins/metabolism
Human Umbilical Vein Endothelial Cells
Humans
Ion Channels/genetics/metabolism
*Mechanotransduction, Cellular
Phosphoproteins/analysis/metabolism
Protein Interaction Maps
p21-Activated Kinases/metabolism
rac GTP-Binding Proteins/metabolism
rhoA GTP-Binding Protein/metabolism
Abstract:
The vascular system is precisely regulated to adjust blood flow to organismal demand, thereby guaranteeing adequate perfusion under varying physiological conditions. Mechanical forces, such as cyclic circumferential stretch, are among the critical stimuli that dynamically adjust vessel distribution and diameter, but the precise mechanisms of adaptation to changing forces are unclear. We find that endothelial monolayers respond to cyclic stretch by transient remodeling of the vascular endothelial cadherin-based adherens junctions and the associated actomyosin cytoskeleton. Time-resolved proteomic profiling reveals that this remodeling is driven by calcium influx through the mechanosensitive Piezo1 channel, triggering Rho activation to increase actomyosin contraction. As the mechanical stimulus persists, calcium signaling is attenuated through transient down-regulation of Piezo1 protein. At the same time, filamins are phosphorylated to increase monolayer stiffness, allowing mechanoadaptation to restore junctional integrity despite continuing exposure to stretch. Collectively, this study identifies a biphasic response to cyclic stretch, consisting of an initial calcium-driven junctional mechanoresponse, followed by mechanoadaptation facilitated by monolayer stiffening.
