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

Area of Science:

• Vascular biology
• Cellular physiology
• Infectious disease research

Background:

• Blood vessel leakage is critical in infectious diseases like sepsis and COVID-19, leading to organ failure.
• Current treatments for improving vascular barrier function are limited.
• Maintaining vascular integrity is essential for preventing disease progression.

Purpose of the Study:

• To investigate the potential of osmolarity modulation in enhancing vascular barrier function.
• To explore hyperosmotic adaptation as a therapeutic strategy for infectious diseases.
• To understand the molecular mechanisms underlying osmolarity-induced vascular stabilization.

Main Methods:

• Utilized 3D human vascular microphysiological systems for high-throughput analysis.
• Employed automated permeability quantification to assess vascular barrier function.
• Integrated genetic and protein level analyses to elucidate molecular pathways.

Main Results:

• Hyperosmotic exposure (>500 mOsm L⁻¹) significantly enhanced vascular barrier function (>7-fold) within 24-48 hours.
• Hypo-osmotic exposure (<200 mOsm L⁻¹) disrupted vascular barrier function.
• Hyperosmolarity upregulated vascular endothelial-cadherin, F-actin, and cell-cell junction tension, mechanically stabilizing the barrier.
• Improved barrier function persisted after chronic inflammatory cytokine exposure and via Yes-associated protein signaling.

Conclusions:

• Osmolarity modulation, particularly hyperosmotic exposure, can significantly improve vascular barrier function.
• Hyperosmotic adaptation provides mechanical stabilization of the vascular barrier through specific molecular pathways.
• Osmolarity modulation represents a promising therapeutic strategy to protect vascular integrity and prevent severe infectious disease progression.