Targeting Wnt/β-Catenin Activated Cells with Dominant-Negative N-cadherin to Reduce Neointima Formation

Area of Science:

• Cardiovascular Biology
• Gene Therapy
• Vascular Smooth Muscle Cell Biology

Background:

• Coronary artery bypass graft failure within 10 years is common, primarily due to intimal thickening.
• Intimal thickening involves vascular smooth muscle cell (VSMC) proliferation and migration.
• Targeting specific VSMC activation pathways may prevent graft failure.

Purpose of the Study:

• To investigate a gene therapy approach for reducing intimal thickening in vein grafts.
• To determine if dominant-negative N-cadherin (dn-N-cadherin) selectively targets Wnt/β-catenin/T cell factor (TCF) activated VSMCs.
• To assess the efficacy of this approach in reducing intimal thickening both ex vivo and in vivo.

Main Methods:

• Developed an adenovirus encoding dn-N-cadherin under the TCF promoter (Ad-TOP-dn-N-cadherin).
• Tested Ad-TOP-dn-N-cadherin in cultured human VSMCs, ex vivo human saphenous vein organ cultures, and an in vivo mouse carotid artery ligation model.
• Assessed VSMC apoptosis, migration, proliferation, intimal thickening, and endothelial cell coverage.

Main Results:

• Ad-TOP-dn-N-cadherin specifically expressed dn-N-cadherin in activated VSMCs, increasing apoptosis and inhibiting migration without affecting proliferation.
• Ex vivo studies showed Ad-TOP-dn-N-cadherin significantly increased VSMC apoptosis and suppressed intimal thickening by 75% without harming endothelial cells.
• In vivo studies demonstrated a significant reduction in intimal thickening at 21 days post-treatment in the mouse carotid artery ligation model.

Conclusions:

• A novel gene therapy approach using Ad-TOP-dn-N-cadherin effectively and selectively reduces VSMC-driven intimal thickening.
• This strategy shows promise for preventing late vein graft failure.
• Further investigation is warranted to explore its clinical applicability.