A Self-Sustaining Mechanism for Endothelial Tension Maintenance Through GqGPCR Signaling

The vascular endothelium maintains homeostasis by acting as a selective barrier, permitting the exchange of nutrients, immune cells, and signaling molecules while restricting pathogens. It further regulates vascular function by generating and sustaining mechanical tension. Aging and disease alter the vascular environment and disrupt the regulation of endothelial tension, contributing to vascular diseases such as hypertension and atherosclerosis. Although endothelial mechanics are influenced by the cellular environment, the mechanisms that enable endothelial cells (ECs) to maintain tension over time remain poorly understood. Here, we demonstrate that confluent human umbilical vein endothelial cells (HUVECs) sustain stable tension for at least three days in the absence of external chemical or mechanical stimuli, indicating the presence of an intrinsic, active mechanism for long-term tension maintenance. Imaging of an EC multicellular ensemble shows a collective phenomenon where diacylglycerol release consistently precedes a rise in intracellular contractility. This contractility propagates to neighboring cells, wherein we identify a Gq-G-protein-coupled receptor (GqGPCR) signaling pathway as a key regulator driving force generation in ECs. The persistence of this signaling sequence in the absence of exogenous agonists suggests a force-induced-force-generation mechanism that coordinates tension maintenance across the monolayer. Together, these findings demonstrate that ECs actively regulate tension through continuous GqGPCR signaling, revealing tension maintenance as a dynamic, collective process. This work provides new insight into how vascular tissues preserve mechanical homeostasis and suggests potential therapeutic targets for vascular endothelial dysfunction and age-related vascular stiffening. New and NoteworthyThis study reveals that endothelial cells actively maintain mechanical tension through continuous GqGPCR signaling rather than passive mechanical properties. We demonstrate that DAG signaling consistently precedes contractility increases, even without chemical stimulation, suggesting that intercellular forces alone can activate this pathway. This "force-induced-force-generation" mechanism represents a potential therapeutic target for vascular dysfunction. Our findings reframe tension maintenance as a dynamic, collectively regulated process in the vascular endothelium.