Healing the injured vessel wall using microRNA-facilitated gene delivery
Mark W. Feinberg
Mark W. Feinberg
View: Text | PDF
Commentary

Healing the injured vessel wall using microRNA-facilitated gene delivery

Abstract

Drug-eluting stents have emerged as potent weapons in the treatment of patients with symptomatic coronary artery disease by reducing restenosis rates; however, a significant clinical consequence of these stents is delayed reendothelialization, which may increase the risk of late stent thrombosis. In this issue of the JCI, Santulli and colleagues generated an adenovirus that expresses the cyclin-dependent kinase inhibitor p27Kip1 (p27) and bears four tandem copies of target sequences for the endothelial cell–enriched microRNA (miRNA) miR-126-3p (Ad-p27-126TS) in an attempt to specifically reduce proliferation of vascular smooth muscle cells, but not endothelial cells. Indeed, delivery of Ad-p27-126TS to balloon-injured arteries in rats not only induced faster and more complete reendothelialization, but also effectively improved neointimal hyperplasia, hypercoagulability, and vasoreactivity. Collectively, these findings provide a cogent foundation for the potential therapeutic use of miRNA-facilitated gene delivery strategies to heal vessel wall injury.

Authors

Mark W. Feinberg

×

Figure 1

miRNA-facilitated gene delivery of p27 to the injured vessel wall reduces neointimal hyperplasia and improves reendothelialization.

Options: View larger image (or click on image) Download as PowerPoint
miRNA-facilitated gene delivery of p27 to the injured vessel wall reduce...
Carotid artery injury, such as occurs following balloon inflation, results in neointimal hyperplasia, increased extracellular matrix deposition, and loss of vessel endothelium, all of which increase thrombotic risk. Treatment with adenovirus control (Ad-GFP) does not alter injury-induced vessel damage. Following carotid artery injury, adenoviral delivery of an adenovirus for p27 (Ad-27) inhibits neointimal hyperplasia, but does not improve reendothelialization. Santulli and colleagues (21) have demonstrated that local delivery of an adenovirus bearing four tandem copies of target sequences for miR-126-3p (Ad-p27-126TS) reduces VSMC proliferation, but not EC proliferation. Because of the markedly higher expression levels of endogenous miR-126-3p in ECs compared with levels in VSMCs, adenoviral p27 overexpression is suppressed in ECs via miR-126-3p–mediated binding of complementary target sequences in the Ad-p27-126TS vector. Consequently, neointimal hyperplasia is reduced and endothelial growth and coverage are increased, leading to improved thrombotic risk and vasoreactivity.