Resveratrol promotes endothelial cell wound healing under laminar shear stress through an estrogen receptor-α-dependent pathway.
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.
Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, Louisiana;
Arif
A
Yurdagul
James J
JJ
Kleinedler
Marshall C
MC
McInnis
Alok R
AR
Khandelwal
Allyson L
AL
Spence
A Wayne
AW
Orr
Tammy R
TR
Dugas
D000818:Animals; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D051379:Mice; D008815:Mice, Inbred Strains; D023421:Models, Animal; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D012039:Regional Blood Flow / Q000502:physiology; D000077185:Resveratrol; D033081:Shear Strength / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013267:Stilbenes / Q000494:pharmacology*; D013314:Stress, Mechanical; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology
D002317:Cardiovascular Agents; D047628:Estrogen Receptor alpha; D013267:Stilbenes; D052250:Nitric Oxide Synthase Type III; D048049:Extracellular Signal-Regulated MAP Kinases; D017239:Paclitaxel; D000077185:Resveratrol
endothelial; estrogen receptor; resveratrol; sheer stress; wound healing