It has been appreciated over the past two decades that arterial remodelling, in addition to intimal hyperplasia, contributes significantly to the degree of restenosis that develops following revascularization procedures. Remodelling appears to be an adventitia-based process that is contributed to by multiple factors including cytokines and growth factors that regulate extracellular matrix or phenotypic transformation of vascular cells including myofibroblasts. In this review, we summarize the currently available information from animal models as well as clinical investigations regarding arterial remodelling. The factors that contribute to this process are presented with an emphasis on potential therapeutic methods to enhance favourable remodelling and prevent restenosis.

Intimal hyperplasia produces restenosis (re-narrowing) of the vessel lumen following vascular intervention. Drugs that inhibit intimal hyperplasia have been developed, however there is currently no clinical method of perivascular drug-delivery to prevent restenosis following open surgical procedures. Here we report a poly(ε-caprolactone) (PCL) sheath that is highly effective in preventing intimal hyperplasia through perivascular delivery of rapamycin. We first screened a series of bioresorbable polymers, i.e., poly(lactide-co-glycolide) (PLGA), poly(lactic acid) (PLLA), PCL, and their blends, to identify desired release kinetics and sheath physical properties. Both PLGA and PLLA sheaths produced minimal (<30%) rapamycin release within 50 days in PBS buffer. In contrast, PCL sheaths exhibited more rapid and near-linear release kinetics, as well as durable integrity (>90 days) as evidenced in both scanning electron microscopy and subcutaneous embedding experiments. Moreover, a PCL sheath deployed around balloon-injured rat carotid arteries was associated with a minimum rate of thrombosis compared to PLGA and PLLA. Morphometric analysis and immunohistochemistry revealed that rapamycin-loaded perivascular PCL sheaths produced pronounced (85%) inhibition of intimal hyperplasia (0.15±0.05 vs 1.01±0.16), without impairment of the luminal endothelium, the vessel’s anti-thrombotic layer. Our data collectively show that a rapamycin-loaded PCL delivery system produces substantial mitigation of neointima, likely due to its favorable physical properties leading to a stable yet flexible perivascular sheath and steady and prolonged release kinetics. Thus, a PCL sheath may provide useful scaffolding for devising effective perivascular drug delivery particularly suited for preventing restenosis following open vascular surgery.

Background Three major processes, constrictive vessel remodeling, intimal hyperplasia and retarded re-endothelialization, contribute to restenosis after vascular reconstructions. Clinically used drugs inhibit intimal hyperplasia but delay re-endothelialization and also cause constrictive remodeling. Here we have examined halofuginone (HF), a herbal derivative, for its beneficial effects on vessel remodeling and differential inhibition of intimal hyperplasia versus re-endothelialization. Methods and Results Two weeks after perivascular application to balloon-injured rat common carotid arteries, HF versus vehicle (n=6 animals) enlarged luminal area 2.14 fold by increasing vessel size (adaptive remodeling, 123%), reducing intimal hyperplasia (74.3%) without inhibiting re-endothelialization. Consistent with its positive effect on vessel expansion, HF reduced collagen type-1 (but not type-3) production in injured arteries as well as that from adventitial fibroblasts in vitro. In support of its differential effects on intimal hyperplasia versus re-endothelialization, HF produced greater inhibition of vascular smooth muscle cell versus endothelial cell proliferation at concentrations around 50 nM. Furthermore, HF at 50 nM effectively blocked Smad3 phosphorylation in smooth muscle cells which is known to promote smooth muscle cell proliferation, migration, and intimal hyperplasia, but HF had no effect on phospho-Smad3 in endothelial cells. Conclusions Periadventitial delivery of HF dramatically increased lumen patency via adaptive remodeling and selective inhibition of intimal hyperplasia without affecting endothelium recovery. HF is the first reported small molecule that has favorable effects on all three major processes involved in restenosis.

Restenosis, or arterial lumen re-narrowing, occurs in 30–50% of the patients undergoing angioplasty. Adaptive remodeling is the compensatory enlargement of the vessel size, and has been reported to prevent the deleterious effects of restenosis. Our previous studies have shown that elevated transforming growth factor (TGF-β) and its signaling protein Smad3 in the media layer induce adaptive remodeling of angioplastied rat carotid artery accompanying an increase of total collagen in the adventitia. In order to gain insights into a possible role of collagen in Smad3-induced adaptive remodeling, here we have investigated a mechanism of cell–cell communication between medial smooth muscle cells (SMCs) and adventitial fibroblasts in regulating the secretion of two major collagen subtypes. We have identified a preferential collagen-3 versus collagen-1 secretion by adventitial fibroblasts following stimulation by the conditioned medium from the TGF-β1-treated/Smad3-expressing medial smooth muscle cells (SMCs), which contained higher levels of CTGF and IGF2 as compared to control medium. Treating the TGF-β/ Smad3-stimulated SMCs with an siRNA to either CTGF or IGF2 reversed the effect of conditioned media on preferential collagen-3 secretion from fibroblasts. Moreover, recombinant CTGF and IGF2 together stimulated adventitial fibroblasts to preferentially secrete collagen-3 versus collagen-1. This is the first study to identify a preferential secretion of collagen-3 versus collagen-1 from adventitial fibroblasts as a result of TGF-β/Smad3 stimulation of medial SMCs, and that CTGF and IGF2 function together to mediate this signaling communication between the two cell types.