Fibrinogen-induced increased pial venular permeability in mice

Area of Science:

• Neuroscience
• Vascular Biology
• Biochemistry

Background:

• Elevated Fibrinogen (Fg) levels are linked to vascular dysfunction.
• The precise mechanisms by which high Fg impacts cerebrovascular permeability remain under investigation.

Purpose of the Study:

• To test the hypothesis that high Fg levels increase cerebrovascular permeability via matrix metalloproteinase (MMP) activation.
• To elucidate the role of MMP-9 in Fg-induced changes in cerebrovascular integrity.

Main Methods:

• Infusion of Fibrinogen (Fg) or phosphate-buffered saline (PBS) into wild-type (WT) and MMP-9 gene knockout (MMP9-/-) mice.
• Assessment of pial venular leakage using intravital fluorescence microscopy.
• Evaluation of vascular endothelial cadherin (VE-cadherin) and plasmalemmal vesicle-associated protein-1 (PV-1) expression.

Main Results:

• Fg infusion increased pial venular macromolecular leakage in both WT and MMP9-/- mice, more significantly in WT mice.
• Fg infusion led to decreased VE-cadherin and increased PV-1 expression, with less pronounced changes in MMP9-/- mice.
• These findings suggest MMP-9 activation is crucial for Fg-induced alterations in microvascular integrity.

Conclusions:

• Elevated Fibrinogen compromises cerebrovascular integrity through MMP-9 activation.
• Fg-induced changes involve downregulation of VE-cadherin and upregulation of PV-1.
• High Fg levels may play a significant role in cerebrovascular dysfunction and remodeling.