CCM1-ICAP-1 complex controls β1 integrin-dependent endothelial contractility and fibronectin remodeling

Area of Science:

• Vascular Biology
• Cellular Signaling
• Extracellular Matrix Biology

Background:

• The cerebral cavernous malformation (CCM) complex is crucial for blood vessel stability and permeability.
• Loss-of-function mutations in CCM genes cause human cerebral cavernous malformations (CCMs), characterized by fragile, dilated capillaries.
• CCM lesions exhibit endothelium lacking mural cells and altered extracellular matrix (ECM).

Purpose of the Study:

• To investigate the role of the CCM complex in regulating integrin signaling.
• To determine if CCM complex dysfunction impacts β1 integrin activation and downstream signaling pathways.
• To elucidate the mechanisms underlying CCM lesion progression.

Main Methods:

• Investigated CCM1/2 complex association with ICAP-1, a β1 integrin inhibitor.
• Analyzed β1 integrin activation, RhoA-dependent contractility, and ECM remodeling in CCM1/2-deficient and ICAP-1-deficient mouse models.
• Assessed endothelial barrier function and intercellular junction stability.

Main Results:

• CCM1/2 loss destabilized ICAP-1, leading to increased β1 integrin activation and RhoA-dependent contractility.
• Aberrant ECM remodeling and altered force distribution were observed around lesions in CCM-deficient mice.
• ICAP-1 deficiency recapitulated similar vascular defects.
• A positive feedback loop between ECM and cellular tension decreased endothelial barrier function.
• Up-regulation of β1 integrin activation contributes to CCM lesion progression.

Conclusions:

• CCM complex dysfunction promotes CCM lesion progression through increased β1 integrin activation.
• Destabilization of ICAP-1 by CCM loss triggers a cascade of events including increased cell contractility and ECM remodeling.
• These alterations compromise endothelial barrier function and destabilize intercellular junctions, exacerbating CCM pathology.