Restenosis Inhibition and Re-differentiation of TGFβ/Smad3-activated Smooth Muscle Cells by Resveratrol.
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.
Department of Surgery, University of Wisconsin, 5151 Wisconsin Institute for Medical Research, 1111 Highland Ave, Madison, WI 53705, USA.|Department of Urology, Capital Medical University Beijing Friendship Hospital, N0. 95, Yong'an Road, Xicheng district, Beijing, China.
Yichen
Y
Zhu
University of Wisconsin Hospital and Clinics, 600 Highland Ave, Madison, WI 53792, USA.
Toshio
T
Takayama
Department of Surgery, University of Wisconsin, 5151 Wisconsin Institute for Medical Research, 1111 Highland Ave, Madison, WI 53705, USA.
Bowen
B
Wang
Department of Surgery, University of Wisconsin, 5151 Wisconsin Institute for Medical Research, 1111 Highland Ave, Madison, WI 53705, USA.
Alycia
A
Kent
Department of Surgery, University of Wisconsin, 5151 Wisconsin Institute for Medical Research, 1111 Highland Ave, Madison, WI 53705, USA.
Mengxue
M
Zhang
Department of Biomedical Engineering, University of Wisconsin, 5009 Wisconsin Institute for Medical Research, 1111 Highland Ave, Madison, WI 53705, USA.
Bernard Y K
BY
Binder
Department of Surgery, University of Wisconsin, 5151 Wisconsin Institute for Medical Research, 1111 Highland Ave, Madison, WI 53705, USA.
Go
G
Urabe
School of Pharmacy and Department of Chemistry, University of Wisconsin, Madison, WI 53705, USA.
Yatao
Y
Shi
Department of Surgery, University of Wisconsin, 5151 Wisconsin Institute for Medical Research, 1111 Highland Ave, Madison, WI 53705, USA.
Daniel
D
DiRenzo
Department of Surgery, University of Wisconsin, 5151 Wisconsin Institute for Medical Research, 1111 Highland Ave, Madison, WI 53705, USA.
Shakti A
SA
Goel
Department of Surgery, University of Wisconsin, 5151 Wisconsin Institute for Medical Research, 1111 Highland Ave, Madison, WI 53705, USA.
Yifan
Y
Zhou
University of Wisconsin Hospital and Clinics, 600 Highland Ave, Madison, WI 53792, USA.
Christopher
C
Little
University of Wisconsin Hospital and Clinics, 600 Highland Ave, Madison, WI 53792, USA.
Drew A
DA
Roenneburg
Department of Surgery, University of Wisconsin, 5151 Wisconsin Institute for Medical Research, 1111 Highland Ave, Madison, WI 53705, USA.
Xu Dong
XD
Shi
School of Pharmacy and Department of Chemistry, University of Wisconsin, Madison, WI 53705, USA.|School of Life Sciences, Tianjin University, No. 92 Weijin Road, Nankai District, Tianjin 300072, China.
Lingjun
L
Li
Department of Biomedical Engineering, University of Wisconsin, 5009 Wisconsin Institute for Medical Research, 1111 Highland Ave, Madison, WI 53705, USA.
William L
WL
Murphy
Department of Surgery, University of Wisconsin, 5151 Wisconsin Institute for Medical Research, 1111 Highland Ave, Madison, WI 53705, USA.|University of Wisconsin Hospital and Clinics, 600 Highland Ave, Madison, WI 53792, USA.
K Craig
KC
Kent
Department of Anesthesiology, Medical College, Wuhan University, 169 Donghu Road, Wuhan, Hubei, PR China.
Jianjuan
J
Ke
Department of Surgery, University of Wisconsin, 5151 Wisconsin Institute for Medical Research, 1111 Highland Ave, Madison, WI 53705, USA.
Lian-Wang
LW
Guo
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D023903:Coronary Restenosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D000975:Antioxidants; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D013267:Stilbenes; D016212:Transforming Growth Factor beta; D000077185:Resveratrol