Abstract
To date, there is no periadventitial drug delivery method available in the clinic to prevent restenotic failure of open vascular reconstructions. Resveratrol is a promising anti-restenotic natural drug but subject to low bioavailability when systemically administered. In order to reconcile these two prominent issues, we tested effects of periadventitial delivery of resveratrol on all three major pro-restenotic pathologies including intimal hyperplasia (IH), endothelium impairment, and vessel shrinkage. In a rat carotid injury model, periadventitial delivery of resveratrol either via Pluronic gel (2-week), or polymer sheath (3-month), effectively reduced IH without causing endothelium impairment and vessel shrinkage. In an in vitro model, primary smooth muscle cells (SMCs) were stimulated with elevated transforming growth factor (TGFβ) and its signaling protein Smad3, known contributors to IH. TGFβ/Smad3 up-regulated Kruppel-like factor (KLF5) protein, and SMC de-differentiation which was reversed by KLF5 siRNA. Furthermore, TGFβ/Smad3-stimulated KLF5 production and SMC de-differentiation were blocked by resveratrol via its inhibition of the Akt-mTOR pathway. Concordantly, resveratrol attenuated Akt phosphorylation in injured arteries. Taken together, periadventitial delivery of resveratrol produces durable inhibition of all three pro-restenotic pathologies — a rare feat among existing anti-restenotic methods. Our study suggests a potential anti-restenotic modality of resveratrol application suitable for open surgery.
Highlights
Post-operative vessel re-narrowing occurs in a great number of patients undergoing vascular reconstructions because of intimal hyperplasia (IH) and/or constrictive vessel remodeling[1]
We found that TGFβ/Smad[3] treatment de-differentiated smooth muscle cells (SMCs) via up-regulation of KLF5 protein, and resveratrol could re-differentiate those cells by blocking KLF5 up-regulation
While we previously showed that TGFβ/Smad[3] stimulated Akt phosphorylation via direct protein interactions[32], Brito et al reported that resveratrol inhibited the Akt-mTOR pathway in SMCs in vitro[34]
Summary
Post-operative vessel re-narrowing (or restenosis) occurs in a great number of patients undergoing vascular reconstructions because of intimal hyperplasia (IH) and/or constrictive vessel remodeling[1]. Drug-eluting stents are used for the management of restenosis following angioplasty, but this method cannot be applied to open surgeries[18] In this specific context, to evaluate the potential of resveratrol as a candidate anti-restenotic therapeutic for open surgery, we employed a periadventitial[15], local (as opposed to systemic) delivery approach to determine its full-spectrum impact on the major pathological processes contributing to restenosis, including IH, endothelium damage, as well as constrictive remodeling. Activated SMCs undergo de-differentiation, as manifested by reduced expression of contractile proteins[22] including calponin, smooth muscle myosin heavy chain (SM-MHC), and smooth muscle actin (α-SMA)[20] They migrate into the intima, proliferate, and form a highly cellular neointima layer intruding into the lumen (restenosis)[23]. It is not known whether TGFβ/Smad3-stimulated SMC de-differentiation is related to KLF5
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