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

Abstract

In infectious disease such as sepsis and COVID‐19, blood vessel leakage treatment is critical to prevent fatal progression into multi‐organ failure and ultimately death, but the existing effective therapeutic modalities that improve vascular barrier function are limited. Here, this study reports that osmolarity modulation can significantly improve vascular barrier function, even in an inflammatory condition. 3D human vascular microphysiological systems and automated permeability quantification processes for high‐throughput analysis of vascular barrier function are utilized. Vascular barrier function is enhanced by >7‐folds with 24–48 h hyperosmotic exposure (time window of emergency care; >500 mOsm L−1) but is disrupted after hypo‐osmotic exposure (<200 mOsm L−1). By integrating genetic and protein level analysis, it is shown that hyperosmolarity upregulates vascular endothelial‐cadherin, cortical F‐actin, and cell–cell junction tension, indicating that hyperosmotic adaptation mechanically stabilizes the vascular barrier. Importantly, improved vascular barrier function following hyperosmotic exposure is maintained even after chronic exposure to proinflammatory cytokines and iso‐osmotic recovery via Yes‐associated protein signaling pathways. This study suggests that osmolarity modulation may be a unique therapeutic strategy to proactively prevent infectious disease progression into severe stages via vascular barrier function protection.

Hypertonic treatment of acute respiratory distress syndrome

“…Experimental evidence reveals that infusion of hyperosmolar sucrose in lung venular capillaries enhances the capillary barrier function, as quantified by the capillary hydraulic conductivity; this finding suggests that hyperosmolar therapy might be beneficial in lung inflammatory disease (Safdar et al, 2003). The combined genetic-and protein-level analysis of Kang et al (2023) leads to a similar conclusion. This study demonstrated that microcirculatory hyperosmolarity upregulates cell-cell junction tension, showing that intravascular hyperosmotic conditions mechanically stabilize the vascular barrier, thus providing an additional therapeutic effect.…”

Vascular microphysiological systems

“…Often, permeability is quantified to assess the vascular inflammatory response. For example, one study exposed vasculature to inflammatory cytokines [tumor necrosis factor-α (TNF-α) or lipopolysaccharides (LPS)] and explored using hyperosmolarity to preserve barrier integrity, which occurred via upregulation cytoskeletal proteins and cell junctions [11]. In addition to soluble factors such as TNF-α and LPS modifying permeability, activated immune cells also may cause alterations in barrier function [12].…”

Bacterial-host adhesion dominated by collagen subtypes remodeled by osmotic pressures

“…Osmotic homeostasis profoundly regulates cell cycle arrest 9 , immunity [10][11][12] , migration and other cell functions and behaviors 13 . It is reported that hypertonic osmotic pressure modulates vascular barrier function and proactively prevents infectious diseases from progressing to a severe stage 14 . There is growing evidence that hyperosmolality induced by highsalt diet impairs antimicrobial neutrophil responses 10 , triggers autoimmune disease 12 , and enhances pro-inflammatory activity in macrophages 11 .…”