Impaired VE-cadherin/beta-catenin expression mediates endothelial cell degeneration in dilated cardiomyopathy

Area of Science:

• Cardiovascular Biology
• Cellular Biology
• Molecular Medicine

Background:

• Vascular endothelial growth factor (VEGF)-A, angiopoietin (Ang), and VE-cadherin interactions regulate endothelial cell (EC) survival.
• Cardiac VEGF-A expression is reduced in dilated cardiomyopathy (DCM), but the role of VE-cadherin/Ang signaling remains unclear.

Purpose of the Study:

• To investigate the function of VE-cadherin/beta-catenin and angiopoietin signaling in the myocardium of patients with DCM.
• To determine the relationship between VE-cadherin/beta-catenin, angiopoietins, and endothelial cell degeneration in DCM.

Main Methods:

• Examined myocardial expression of VE-cadherin/beta-catenin, Ang-1, Ang-2, and Tie-2 in DCM, ischemic cardiomyopathy (ICM), and control subjects using real-time RT-PCR, Western blotting, and immunocytochemistry.
• Quantified endothelial cell degeneration via transmission electron microscopy (TEM).
• Utilized RNA interference and VEGF manipulation in cultured cells to explore molecular interplay.

Main Results:

• VE-cadherin/beta-catenin expression was significantly downregulated in DCM but not ICM.
• Ang-2 expression was downregulated and Tie-2 protein upregulated in both DCM and ICM.
• Higher rates of endothelial cell degeneration were observed in DCM compared to ICM, with VE-cadherin gene silencing mimicking DCM-related EC pathology.

Conclusions:

• Endothelial cell survival is impaired in DCM, linked to VE-cadherin/beta-catenin dysfunction, likely independent of VEGF.
• Targeting VE-cadherin presents a potential therapeutic strategy for DCM-associated endothelial cell pathology.