Histamine alters endothelial barrier function at cell-cell and cell-matrix sites

Area of Science:

• Endothelial biology
• Cellular biophysics
• Integrative physiology

Background:

• Endothelial barrier integrity is crucial for regulating vascular permeability.
• Histamine is a known mediator of endothelial barrier dysfunction.
• The precise mechanisms by which histamine affects endothelial cell adhesion and cytoskeletal networks remain incompletely understood.

Purpose of the Study:

• To mathematically model endothelial barrier resistance.
• To elucidate the role of histamine in regulating endothelial barrier function.
• To investigate the contributions of cell-cell, cell-matrix, and transcellular resistances to histamine-induced barrier changes.

Main Methods:

• Mathematical modeling of endothelial cell-covered electrode resistance.
• Measurement of transendothelial resistance in confluent and subconfluent human umbilical vein endothelial cells (HUVECs).
• Validation using antibodies against cadherin-5 and E-cadherin transfection, alongside transmission electron microscopy.

Main Results:

• Histamine rapidly decreased transendothelial resistance, primarily by reducing cell-cell resistance in confluent HUVECs.
• Barrier restoration involved initial increases in cell-matrix resistance, followed by increases in cell-cell resistance.
• Histamine's effect on cell-cell resistance was dependent on cell-cell contact, as shown in subconfluent cells and experiments with cadherin antibodies and E-cadherin expression.

Conclusions:

• Histamine disrupts endothelial barrier function by specifically targeting cell-cell adhesion.
• Barrier restoration is a multi-step process involving both cell-matrix and cell-cell adhesion.
• The findings provide a quantitative understanding of histamine's effects on endothelial barrier dynamics and cytoskeletal regulation.