Isthmin is a novel vascular permeability inducer that functions through cell-surface GRP78-mediated Src activation

Area of Science:

• Cell Biology
• Physiology
• Molecular Medicine

Background:

• Isthmin (ISM) is a secreted protein known as an angiogenesis inhibitor.
• ISM interacts with cell-surface receptors, including glucose-regulated protein 78 kDa (GRP78) and αvβ5 integrin.
• αvβ5 integrin is implicated in pulmonary vascular permeability (VP), and ISM is abundant in mouse lungs.

Purpose of the Study:

• To investigate the role of Isthmin (ISM) in regulating pulmonary vascular permeability (VP).
• To elucidate the molecular mechanisms by which ISM affects VP.
• To determine ISM's contribution to acute lung injury (ALI).

Main Methods:

• In vitro studies using endothelial cell monolayers.
• In vivo experiments in mice, including intradermal and intravenous administration of recombinant ISM (rISM).
• Molecular and biochemical analyses to identify signaling pathways involved, including Src activation and protein interactions. Studies utilizing specific chemical inhibitors and antibodies.

Main Results:

• Recombinant ISM (rISM) dose-dependently increased endothelial monolayer permeability in vitro and dermal VP in mice.
• Systemic rISM administration caused significant lung vascular hyperpermeability.
• ISM-GRP78 interaction activated Src kinase, leading to adherens junction protein disruption and enhanced VP. Apoptosis contributed indirectly.
• ISM was upregulated in LPS-induced ALI mouse lungs, and anti-GRP78 antibody treatment attenuated lung vascular hyperpermeability.

Conclusions:

• Isthmin (ISM) is a novel inducer of vascular permeability (VP).
• ISM functions via GRP78-mediated Src activation and apoptosis induction.
• ISM contributes to the pulmonary vascular hyperpermeability observed in LPS-induced ALI.