Restenosis Inhibition and Re-differentiation of TGFβ/Smad3-activated Smooth Muscle Cells by Resveratrol

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.

Krüppel-Like Factors in Vascular Inflammation: Mechanistic Insights and Therapeutic Potential

“…Contrary to its inductive effect on endothelial KLF2, resveratrol has been shown to decrease TGF-β-mediated KLF5 transcription ( 155 ). Through its inhibition of the Akt-mTOR pathway, resveratrol is capable of blocking KLF5-driven VSMC dedifferentiation, thereby preventing intimal hyperplasia.…”

Analysis of Combined Transcriptomes Identifies Gene Modules that Differentially Respond to Pathogenic Stimulation of Vascular Smooth Muscle and Endothelial Cells

“…Therefore, the JUN module appears to provide ideal intervention targets, inhibition of which would attenuate SMC hyperplasia while protecting ECs. Indeed, our recent report suggests that keeping the Klf5 protein from up-regulation is a probable approach to attenuating SMC phenotype change and neointima formation while enhancing endothelial recovery 42 .…”

Resveratrol and the Interaction between Gut Microbiota and Arterial Remodelling

“…In a rat carotid artery injury model, Intraperitoneal injection of resveratrol inhibits intimal hyperplasia [71]. In addition, periadventitial application of resveratrol has shown significant improvements in intimal hyperplasia, impairment of re-endothelialization and constrictive arterial remodelling, which are the three major pathologies contributing to restenosis [72]. Periadventitial delivery of resveratrol has a greater neointima-inhibiting effect (86%) than systemic resveratrol administration.…”

“…Periadventitial delivery of resveratrol has a greater neointima-inhibiting effect (86%) than systemic resveratrol administration. Moreover, resveratrol promotes post-surgery endothelial recovery without causing constrictive arterial remodelling [72]. These are compelling advantages compared to the current drug-eluting stents used in clinical settings.…”

“…TGF-β1 is an important profibrogenic factor that induces the proliferation of VSMCs and collagen secretion [98,99]. Resveratrol has been demonstrated to block the TGF-β1-stimulated KLF5 production and VSMC de-differentiation [72]. Advanced glycation end-products (AGEs) stimulate non-enzymatic protein glycation forming irreversible cross-links in proteins like collagen.…”