Cellular and extracellular modifications induced by diabetic conditions in tissue engineered blood vessels

Purpose: To determine the fate of tissue engineered blood vessels in the diabetic environment. Elevated levels of blood glucose and lipids interact irreversibly with long-lived proteins, such as collagen and elastin from the... [ view full abstract ]

Purpose: To determine the fate of tissue engineered blood vessels in the diabetic environment. Elevated levels of blood glucose and lipids interact irreversibly with long-lived proteins, such as collagen and elastin from the blood vessel wall, via oxidation and crosslinking, resulting in formation of advanced glycation end products (AGEs) and vascular stiffening. Cells respond by endothelial dysfunction and pathological remodeling of the media, contributing to the onset and progression of vascular disease. Together, these changes result in activation of inflammation, impaired healing, fibrosis, and calcification.
Methods: Acellular scaffolds prepared from renal arteries were treated with penta galoyl glucose (PGG), an antioxidant elastin-binding polyphenol, and seeded with adipose stem cells (ASCs) isolated from streptozotocin-induced diabetic rats. Constructs were analyzed for glycoxidation, inflammation and calcification after subdermal implantation as autologous cell seeded grafts and by end-to-end anastomoses to the aorta. Cells seeded into scaffolds and placed in high-glucose media in bioreactors were analyzed by gene arrays and immunofluorescence.

Results: PGG-treated scaffolds maintained good patency, undetectable dilatation and well-preserved elastin in the circulatory abdominal aorta model in rats. ASCs seeded on scaffolds diminished macrophage infiltration, while simultaneously allowed M2 macrophage polarization. PGG-treatment and ASC seeding inhibited scaffold calcification and expression of osteogenic proteins. In bioreactor, vascular cells maintained long-term viability after exposure to high glucose-containing media, expressed carboxymethyl-lysine and AGE receptors and secreted lower levels of MMPs.

Conclusion: The antioxidative properties of PGG and the immunomodulatory properties of ASCs prevented vascular scaffold deterioration and calcification under the hostile diabetic milieu.