Date of Award
Doctor of Philosophy (PhD)
LaDisa, John F.
LaDisa, John F.
Audi, Said H.
Stents used to decrease cardiovascular risk in patients with type 2 diabetes mellitus (T2DM) are prone to increased rates of restenosis. The mechanisms are incompletely elucidated, but low wall shear stress (WSS) and altered intracellular signaling likely contribute. We tested the hypothesis that neointimal hyperplasia (NH) after bare-metal stenting is due to vascular remodeling (enhanced formation of advanced glycation end-products (AGEs), increased downstream vascular resistance (DVR), and decreased WSS), and that decreasing AGEs with ALT-711 (Alagebrium) mitigates this response.
Stents were implanted into the abdominal aorta of Zucker lean (ZL), obese (ZO), and diabetic (ZD) rats. After 21 days, the stented region was sectioned for NH quantification or casted and imaged for regional estimation of WSS and local intrastrut WSS by computational fluid dynamics. The thoracic and abdominal aorta, carotid, iliac, femoral and arterioles in cremaster muscle were harvested to detect AGEs related collagen cross-linking, and protein expression including transforming growth factor beta (TGFβ) and receptor for AGE (RAGE).
A trend toward elevated DVR was observed, whereas blood flow (BF) and intrastrut TAWSS were significantly decreased in ZD compared to ZL and ZO rats (eg. TAWSS: 14.5 ± 1.9 vs 30.6 ± 1.6 and 25.4 ± 2.2 dyn/cm2, respectively; mean±SEM P<0.05). Intrastrut NH was increased in ZO but not ZD rats. ALT-711 reduced DVR in ZD rats (15.6±2.5x105 to 8.39±0.6x105 dyn∙s/cm5), while decreasing NH (ZL: 7.7±1.0 to 4.3±0.9%; ZO: 12.0±1.5 to 4.9±0.8%; ZD: 9.4±0.7 to 3.7±0.4%) and causing similar regional TAWSS results in all groups. AGEs related collagen cross-linking was elevated in the arterioles of ZD rats, but alleviated by ALT-711. No consistent differences in RAGE or TGFβ expression were observed in treated versus untreated rats.
Remodeling of the distal vasculature appears to play an important role in modulating WSS in T2DM, but WSS alone does not predict NH response as observed under normoglycemia. ALT-711 led to similar values for AGEs related arteriolar collagen cross-linking, BF through the stent, and regional WSS, while decreasing NH in all rats. Although TGFβ and RAGE expression did not appear to be modified by ALT-711, other intracellular signaling pathways remain to be explored.