High Glucose Induced Changes in Human VEC Phenotype in a 3D Hydrogel Derived From Cell-Free Native Aortic Root

Area of Science:

• Cardiovascular Biology
• Cellular Biology
• Diabetic Complications

Background:

• Dysfunctional valvular endothelial cells (VEC) are central to aortic valve disease in diabetes.
• High glucose (HG) induces inflammation in VEC, potentially leading to endothelial to mesenchymal transition (EndMT).
• The role of endothelin (ET) in HG-induced VEC inflammation and EndMT is unclear.

Purpose of the Study:

• To investigate the effects of HG on EndMT in VEC.
• To determine if HG induces ET and its receptors in VEC.
• To assess the role of ET in modulating HG-induced VEC inflammation.

Main Methods:

• Developed a 3D aortic valve model using decellularized extracellular matrix hydrogel and human valvular cells.
• Exposed VEC in the 3D construct to high glucose (HG) conditions.
• Analyzed ultrastructural changes, gene/protein expression (endothelial/mesenchymal markers, inflammatory molecules, ET-1, ET-A, ET-B), and cell adhesiveness; blocked ET-1 receptors.

Main Results:

• HG induced EndMT in VEC, evidenced by altered cell junctions, decreased endothelial markers (CD31, VE-cadherin), and increased mesenchymal markers (α-SMA, vimentin).
• HG upregulated inflammatory molecules (ICAM-1, VCAM-1) and induced ET-1 and its receptors (ET-A, ET-B) in VEC.
• Blocking ET-A and ET-B receptors reduced HG-induced secretion of IL-1β and MCP-1.

Conclusions:

• High glucose directly induces endothelial to mesenchymal transition in valvular endothelial cells.
• Endothelin signaling plays a significant role in high glucose-induced inflammation in VEC.
• Targeting endothelin pathways presents a potential therapeutic strategy for mitigating high glucose-driven aortic valve inflammation.