Introduction: Oral statins reduce intimal hyperplasia (IH) after arterial injury by only ∼25%. Alternative drug delivery systems have gained attention as carriers for hydrophobic drugs. We studied the effects of simvastatin (free vs hyaluronic acid-tagged polysialic acid–polycaprolactone micelles) on vascular smooth muscle cell (VSMC) migration, VSMC proliferation and intimal hyperplasia. We hypothesized both free and micelle containing simvastatin would inhibit VSMC chemotaxis and proliferation, and local statin treatment would be more effective than oral in reducing IH in rats following carotid balloon injury. Methods: VSMCs pretreated with free simvastatin (20 minutes or 20 hours) or simvastatin-loaded micelles underwent chemotaxis and proliferation to platelet-derived growth factor. Next, rats that underwent balloon injury of the common carotid artery received statin therapy—intraluminal simvastatin-loaded micelles prior to injury, periadventitial pluronic gel following injury, or combinations of gel, micelle, and oral simvastatin. After 14 days, morphometric analysis determined the –intimal to medial ratio. Findings were compared to controls receiving oral simvastatin or no statin therapy. Statistical analysis was by analysis of variance for the in vitro experiments and a factorial general linear model for the in vivo experiments. Results: The simvastatin-loaded micelles and free simvastatin inhibited VSMC chemotaxis (54%-60%). IH was induced in all injured vessels. Simvastatin in pluronic gel or micelles reduced IH compared to untreated controls (0.208 ± 0.04 or 0.160 ± 0.03 vs 0.350 ± 0.03, respectively); however, neither gel nor simvastatin-loaded micelles were superior to oral statins (0.261 ± 0.03). Addition of oral statins or combining both local therapies did not provide additional benefit. Micelles were the single greatest contributing factor in IH attenuation. Conclusions: Intraluminally or topically delivered statins reduced IH. The efficacy of single-dose, locally delivered statin alone may lead to novel treatments to prevent IH. The different routes of administration may allow for treatment during endovascular procedures, without the need for systemic therapy.

Background: Ischemia-reperfusion injury (IRI) secondary to acute limb ischemia is a complex clinical phenomenon induced by a variety of pathologies, including arterial embolization, arterial thrombosis, vascular trauma, advanced peripheral vascular disease, traumatic crush injuries, and/or prolonged tourniquet application. The restoration of blood flow and oxygen to the limb after an ischemic period, while necessary, is ultimately the driving force of IRI. The exaggerated inflammation, oxidative stress, and tissue damage caused by IRI often lead to limb dysfunction, limb loss, multi-organ failure, and/or death. While no gold-standard therapy currently exists, various in vitro and in vivo models have been developed to explore potential therapeutic strategies. Currently, pharmacological agents with anti-inflammatory and/or antioxidant properties, as well as non-pharmacological strategies, have been investigated, and some agents show promise in mitigating the effects of lower extremity ischemia-reperfusion injury (IRI). Purpose: In this review article, we provide a comprehensive overview of the pathophysiology of IRI, discuss the local and systemic effects of IRI, and examine the experimental models used to investigate IRI. We also outline the current in vitro and in vivo pharmacological and non-pharmacological interventions studied to reduce IRI.

Lower extremity peripheral arterial disease (PAD) is the atherosclerotic obstruction of the lower extremity arteries that can lead to walking impairment, non-healing open wounds, gangrene or limb loss. It is estimated that PAD affects greater than 200 million people worldwide and is associated with advanced age, tobacco use, diabetes, hypertension, and hypercholesterolemia. Initial management of PAD involves risk factor modification and pharmacologic strategies, including the implementation of statin therapy. Statins, the most commonly used cholesterol lowering medications, also have beneficial pleiotropic (cholesterol independent) effects including improved patency rates from vascular reconstruction, decreased risk of stroke, myocardial infarction and improved survival. In this chapter, we will discuss the relevant clinical trials, prospective observation and retrospective studies that exemplify the effect of statins on PAD. We will then focus on statin’s cellular effects on endothelial and vascular smooth muscle cell function by examining effects on plaque progression, intimal hyperplasia, re-endothelialization, and angiogenesis/arteriogenesis.

Intimal hyperplasia (IH) is a pathologic process that leads to restenosis after treatment for peripheral arterial disease. Heat shock protein 90 (HSP90) is a molecular chaperone that regulates protein maturation. Activation of HSP90 results in increased cell migration and proliferation. 17‑N‑allylamino‑17‑demethoxygeldanamycin (17‑AAG) and 17‑dimethylaminoethylamino‑17‑demethoxygeldanamycin (17‑DMAG) are low toxicity Food and Drug Association approved HSP90 inhibitors. The current study hypothesized that HSP90 inhibition was predicted to reduce vascular smooth muscle cell (VSMC) migration and proliferation. In addition, localized HSP90 inhibition may inhibit post‑angioplasty IH formation. For proliferation, VSMCs were treated with serum‑free media (SFM), 17‑DMAG or 17‑AAG. The selected proliferative agents were SFM, platelet derived growth factor (PDGF) or fibronectin. After three days, proliferation was measured. For migration, VSMCs were treated with SFM, 17‑AAG or 17‑DMAG with SFM, PDGF or fibronectin as chemoattractants. Balloon injury to the carotid artery was performed in rats. The groups included in the present study were the control, saline control, 17‑DMAG in 20% pluronic gel delivered topically to the adventitia or intraluminal delivery of 17‑DMAG. After 14 days, arteries were fixed and sectioned for morphometric analysis. Data was analyzed using ANOVA or a student's t‑test. P<0.05 was considered to indicate a statistically significant difference. The results revealed that 17‑AAG and 17‑DMAG had no effect on cell viability. PDGF and fibronectin also increased VSMC proliferation and migration. Furthermore, both 17‑AAG and 17‑DMAG decreased cell migration and proliferation in all agonists. Topical adventitial treatment with 17‑DMAG after balloon arterial injury reduced IH. HSP90 inhibitors suppressed VSMC proliferation and migration without affecting cell viability. Topical treatment with a HSP90 inhibitor (DMAG) decreased IH formation after arterial injury. It was concluded that 17‑DMAG may be utilized as an effective therapy to prevent restenosis after revascularization.