Resveratrol promotes endothelial cell wound healing under laminar shear stress through an estrogen receptor-α-dependent pathway

Am J Physiol Heart Circ Physiol. 2014 Mar;306(6):H797-806. doi: 10.1152/ajpheart.00892.2013. Epub 2014 Jan 24.


Restenosis is an adverse outcome of angioplasty, characterized by vascular smooth muscle cell (VSMC) hyperplasia. However, therapies targeting VSMC proliferation delay re-endothelialization, increasing the risk of thrombosis. Resveratrol (RESV) inhibits restenosis and promotes re-endothelialization after arterial injury, but in vitro studies assessing RESV-mediated effects on endothelial cell growth contradict these findings. We thus hypothesized that fluid shear stress, mimicking physiological blood flow, would recapitulate RESV-dependent endothelial cell wound healing. Since RESV is an estrogen receptor (ER) agonist, we tested whether RESV promotes re-endothelialization through an ER-α-dependent mechanism. Mice fed a high-fat diet or a diet supplemented with RESV were subjected to carotid artery injury. At 7 days after injury, RESV significantly accelerated re-endothelialization compared with vehicle. In vitro wound healing assays demonstrated that RESV exhibits cell-type selectivity, inhibiting VSMC, but not endothelial cell growth. Under laminar shear stress (LSS), RESV dramatically enhanced endothelial cell wound healing and increased both the activation of extracellular signal-regulated kinase (ERK) and endothelial cell proliferation. Under LSS, small interfering RNA against ER-α, but not endothelial nitric oxide synthase, abolished RESV-induced ERK activation, endothelial cell proliferation, and wound healing. Thus these studies suggest that the EC phenotype induced by LSS better models the prohealing effects of RESV and that RESV and LSS interact to promote an ER-α-dependent mitogenic effect in endothelial cells.

Keywords: endothelial; estrogen receptor; resveratrol; sheer stress; wound healing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiovascular Agents / pharmacology*
  • Carotid Arteries / drug effects
  • Carotid Arteries / metabolism
  • Cell Proliferation / drug effects
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism*
  • Estrogen Receptor alpha / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • In Vitro Techniques
  • Mice
  • Mice, Inbred Strains
  • Models, Animal
  • Nitric Oxide Synthase Type III / metabolism
  • Paclitaxel / pharmacology
  • Regional Blood Flow / physiology
  • Resveratrol
  • Shear Strength / drug effects
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Stilbenes / pharmacology*
  • Stress, Mechanical
  • Wound Healing / drug effects*
  • Wound Healing / physiology


  • Cardiovascular Agents
  • Estrogen Receptor alpha
  • Stilbenes
  • Nitric Oxide Synthase Type III
  • Extracellular Signal-Regulated MAP Kinases
  • Paclitaxel
  • Resveratrol