Document Type




Format of Original

11 p.

Publication Date



American Physiological Society

Source Publication

American Journal of Physiology - Heart and Circulatory Physiology

Source ISSN


Original Item ID

doi: 10.1152/ajpheart.00123.2014


Mechanisms of restenosis in type 2 diabetes mellitus (T2DM) are incompletely elucidated, but advanced glycation end-products (AGEs)-induced vascular remodeling likely contributes. We tested the hypothesis that AGEs-related collagen cross-linking (ARCC) leads to increased downstream vascular resistance (DVR), and altered in-stent hemodynamics, thereby promoting neointimal hyperplasia (NH) in T2DM. We proposed that decreasing ARCC with ALT-711 (Alagebrium) would mitigate this response. Abdominal aortic stents were implanted in Zucker lean (ZL), obese (ZO), and diabetic (ZD) rats. Blood flow, vessel diameter, and wall shear stress (WSS) were calculated after 21 days, and NH was quantified. Arterial segments (aorta, carotid, iliac, femoral, arterioles) were harvested to detect ARCC and protein expression, including transforming growth factor beta (TGFβ) and receptor for AGEs (RAGE). Downstream resistance was elevated (60%), whereas flow and WSS were significantly decreased (44% and 56%) in ZD versus ZL rats. NH was increased in ZO but not ZD rats. ALT-711 reduced ARCC and resistance (46%) in ZD rats, while decreasing NH and producing similar in-stent WSS across groups. No consistent differences in RAGE or TGFβ expression were observed in arterial segments. ALT-711 modified lectin-type oxidized LDL receptor 1 but not RAGE expression by cells on decellularized matrices. In conclusion, ALT-711 decreased ARCC, increased in-stent flow rate, and reduced NH in ZO and ZD rats through RAGE-independent pathways. The study supports an important role for AGEs-induced remodeling within and downstream of stent implantation to promote enhanced NH in T2DM.


Accepted version. American Journal of Physiology: Heart and Circulatory Physiology, Vol. 309, No. 7 (October 1, 2015): H1130-H1140. DOI. © 2015 American Physiological Society. Used with permission.

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