Mechanobiological Adaptation to Hyperosmolarity Enhances Barrier Function in Human Vascular Microphysiolgical System

Abstract

In infectious disease such as sepsis and COVID-19, blood vessel leakagetreatment is critical to prevent fatal progression into multi-organ failure andultimately death, but the existing effective therapeutic modalities that improvevascular barrier function are limited. Here, this study reports that osmolaritymodulation can significantly improve vascular barrier function, even in aninflammatory condition. 3D human vascular microphysiological systems andautomated permeability quantification processes for high-throughput analysisof vascular barrier function are utilized. Vascular barrier function is enhancedby>7-folds with 24–48 h hyperosmotic exposure (time window of emergencycare;>500 mOsm L−1) but is disrupted after hypo-osmotic exposure(<200 mOsm L−1). By integrating genetic and protein level analysis, it isshown that hyperosmolarity upregulates vascular endothelial-cadherin,cortical F-actin, and cell–cell junction tension, indicating that hyperosmoticadaptation mechanically stabilizes the vascular barrier. Importantly, improvedvascular barrier function following hyperosmotic exposure is maintained evenafter chronic exposure to proinflammatory cytokines and iso-osmotic recoveryvia Yes-associated protein signaling pathways. This study suggests thatosmolarity modulation may be a unique therapeutic strategy to proactivelyprevent infectious disease progression into severe stages via vascular barrierfunction protection.