Glypican 1 mechanosensing mediates eNOS uncoupling during hydrostatic pulmonary edema.
Lakshmi Narasimha Rao Thota1, Joaquin Enrique Lopez Rosales1, Ayman Isbatan2
1The University of Arizona, College of Medicine-Tucson, US.
Redox Biology
|September 28, 2025
Summary
Glypican 1 acts as a mechanosensor in lung vasculature, mediating hydrostatic pulmonary edema by regulating endothelial permeability via reactive oxygen species (ROS). Targeting glypican 1 may offer new therapeutic strategies for this condition.
Area of Science:
- Pulmonary vascular research
- Mechanobiology
- Cellular signaling
Background:
- Hydrostatic pulmonary edema results from increased pulmonary capillary pressure, but its molecular mechanisms remain unclear.
- The pulmonary endothelial glycocalyx, particularly heparan sulfate proteoglycans (HSPGs), is implicated in regulating vascular permeability.
- Glypican 1 is a potential mechanosensor within the glycocalyx, but its role in lung edema is not fully understood.
Purpose of the Study:
- To investigate glypican 1 as a mechanosensor in lung vasculature.
- To determine glypican 1's role in the progression of hydrostatic pulmonary edema.
- To elucidate the molecular pathways linking glypican 1 to pressure-induced lung barrier dysfunction.
Main Methods:
- Utilized an isolated perfused lung system with glypican 1 knockout (Gpc1-/-) mice.
- Employed wild-type (WT) mouse lung endothelial cells (MLEC) and human lung microvascular endothelial cells (HLMEC).
- Assessed protein kinase C-alpha (PKCα) and endothelial nitric oxide synthase (eNOS) phosphorylation, reactive oxygen species (ROS) production, and 70 KDa dextran transport under high-pressure conditions.
Main Results:
- Gpc1-/- mice were protected from pressure-induced lung edema, showing reduced dextran transport and ROS production.
- High pressure activated PKCα and phosphorylated eNOS at specific sites in WT cells, increasing ROS via eNOS-dependent pathways.
- Inhibition of eNOS mitigated high-pressure effects; glypican 1 deficiency prevented pathological signaling and stabilized the endothelial barrier.
Conclusions:
- Glypican 1 functions as a mechanosensor in the lung vasculature, mediating high-pressure effects on barrier function through redox-sensitive pathways.
- This mechanism is crucial for hydrostatic pulmonary edema progression and is conserved across species.
- Targeting glypican 1 presents a potential novel therapeutic strategy for hydrostatic pulmonary edema.
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