Resveratrol-Induced Vascular Progenitor Differentiation towards Endothelial Lineage via MiR-21/Akt/β-Catenin Is Protective in Vessel Graft Models

Abstract

Background and PurposeVessel graft failure is typically associated with arteriosclerosis, in which endothelial dysfunction/damage is a key event. Resveratrol has been shown to possess cardioprotective capacity and to reduce atherosclerosis. We aimed to study the influence of resveratrol on the behavior of resident stem cells that may contribute to graft arteriosclerosis.Experimental ApproachVascular resident progenitor cells and embryonic stem cells were treated with resveratrol under differentiating conditions and endothelial markers expression was evaluated. Expression of miR-21 and β-catenin was also tested and exogenously modified. Effects of resveratrol treatment in an ex vivo re-endothelialization model and on mice undergone vascular graft were evaluated.Key ResultsResveratrol induced expression of endothelial markers such as CD31, VE-cadherin and eNOS in both progenitor and stem cells. We demonstrated that resveratrol significantly reduced miR-21 expression, which in turn reduced Akt phosphorylation. This signal cascade diminished the amount of nuclear β-catenin, inducing endothelial marker expression and increasing tube-like formation by progenitor cells. Both the inhibition of miR-21 and the knockdown of β-catenin were able to recapitulate the effect of resveratrol application. Ex vivo, progenitor cells treated with resveratrol produced better endothelialization of the decellularized vessel. Finally, in a mouse model of vessel graft, a resveratrol-enhanced diet was able to reduce lesion formation.Conclusions and ImplicationsWe provide the first evidence that oral administration of resveratrol can reduce neointimal formation in a model of vascular graft and elucidated the underpinning miR-21/Akt/β-catenin dependent mechanism. These findings may support the beneficial effect of resveratrol supplementation for graft failure prevention.

Resveratrol protects neuronal cells from isoflurane‑induced inflammation and oxidative stress‑associated death by attenuating apoptosis via Akt/p38 MAPK signaling

“…Bai et al (16) demonstrated that treatment with resveratrol restrained isoflurane-induced neuroapoptosis by activating the Akt signaling pathway. Campagnolo et al (26) reported that resveratrol reduced neointimal formation in a vascular graft model through microRNA-21/Akt/β-catenin.…”

Phenolic Compounds Exerting Lipid-Regulatory, Anti-Inflammatory and Epigenetic Effects as Complementary Treatments in Cardiovascular Diseases

“…Additionally, the authors showed that vascular progenitor cells treated ex vivo with RSV produced better endothelialization of the decellularized vessels. Moreover, they demonstrated that RSV-enriched diet reduces lesion formation in a mouse model of vessel graft [153].…”

“…This downregulation of miR-20b was proposed to be linked with the potent anti-angiogenic action of RSV in the ischemic myocardium and with the synergic effects of RSV and γ-tocotrienol. An elegant and complex study performed by Campagnolo et al showed that RSV can induce the expression of endothelial markers, such as CD31, VE-cadherin and eNOS in vascular resident progenitor cells and embryonic stem cells [153]. They also demonstrated that RSV significantly reduced miR-21 expression in these cells, which in turn diminished protein kinase B (PKB) phosphorylation.…”

Resveratrol and pterostilbene as a microRNA‐mediated chemopreventive and therapeutic strategy in prostate cancer

“…Resveratrol‐regulated miRNAs also had effects on lipid metabolism in adipose tissues, mitochondrial function in skeletal muscles, and osteoporosis in ovariectomized rats . In addition, resveratrol‐regulated miRNAs played neuroprotective roles and had beneficial effects in preclinical models of Parkinson's and Alzheimer's disease and vessel graft . Finally, anti‐inflammatory effects of resveratrol‐regulated miRNAs have also been reported .…”