20-Hydroxyeicosatetraenoic acid inhibition attenuates balloon injury-induced neointima formation and vascular remodeling in rat carotid arteries.

20-Hydroxyeicosatetraenoic acid (20-HETE) contributes to the migration and proliferation of vascular smooth muscle cells (VSMC) in vitro, but there are few studies that address its effects on vascular remodeling in vivo. The present study determined whether inhibition of 20-HETE production attenuates intimal hyperplasia (IH) and vascular remodeling after balloon injury (BI). Sprague Dawley rats underwent BI of the common carotid artery and were treated with vehicle, 1-aminobenzotriazole (ABT, 50 mg/kg i.p. once daily), or HET0016 (N-hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine) (2 mg/kg s.c. twice daily) for 14 days. Fourteen days after BI and treatment, the animals underwent carotid angiography, and the arteries were harvested for morphometric, enzymatic and immunohistochemical analysis. There was a 96% reduction of angiographic stenosis in the rats treated with 1-ABT. There was a 61 and 66% reduction of the intima/media area ratios in the 1-ABT and HET0016 treated rats compared with the vehicle-treated group. 20-HETE levels were elevated in BI carotid arteries, and the levels were markedly suppressed in the groups treated with 1-ABT and HET0016 (P < 0.001). Immunostaining revealed that the expression of CYP4A enzyme was markedly increased in the neointima of BI arteries, and it colocalized with the expression of smooth muscle-specific actin, indicating increased proliferation of VSMC. An increase in the expression of CYP4A and the production of 20-HETE contributes to neointimal growth in BI rat carotid arteries. Systemic administration 1-ABT or HET0016 prevents the increase in 20-HETE levels and attenuates VSMC migration and proliferation, resulting in a marked reduction in IH and vascular remodeling after endothelial injury.

Angiographic evaluation of the rat carotid balloon injury model.

RATIONALE: The rat carotid balloon-injury (BI) model is a widely used model of intimal hyperplasia (IH) and vascular remodeling. A variable degree of IH after BI has been previously reported, and we have encountered technical challenges and suboptimal results with the original method. OBJECTIVE: To evaluate the original rat carotid artery BI method with the use of micro-angiography. We tested the hypothesis that in order to obtain an optimal arterial response, BI should be limited to the common carotid artery with preservation of blood flow. METHODS AND RESULTS: The left common carotid artery (CCA) was injured by one of three different methods. Carotid angiograms and pathology were examined 14 days after BI. A 2F Fogarty balloon catheter inflated to 2 atm inside the aortic arch would not slide back into the common carotid artery until deflation to 0.5 to 0.7 atm. Four out of five (80%) vessels injured with this method developed excessive inflammation without discernible IH. Six out of nine (66%) arteries that underwent BI limited to the CCA at 2 atm developed the largest angiographic stenosis (p=0.003) and IH (0.20±0.03 mm(2), p=0.028). Ten out of eleven (91%) arteries injured with a variable pressure of 1.5 to 2.2 atm, based on the operator's feedback, developed considerable IH (0.12±0.02 mm(2)). All injured carotid arteries with preserved blood flow on angiography developed IH with intact histological boundaries. CONCLUSIONS: Optimal IH with preservation of histological boundaries is achieved by graded BI limited to the CCA that preserves carotid blood flow.

Aortic response to balloon injury in obese Zucker rats.

The small diameter of the carotid artery is not compatible with the evaluation of clinically available endovascular devices in the carotid balloon-injury (BI) model. We developed an endovascular BI model in the rat descending aorta, whose size is compatible with available endovascular instruments. We also tested the hypothesis that neointima formation is enhanced in the aorta of obese Zucker rats (OZR) compared with lean Zucker rats (LZR). Left external carotid arteriotomies and BI of the thoracic and abdominal aorta were performed by using a balloon catheter. Aortograms and aortic pathology were examined at 2, 4, and 10 wk after BI. At 10 wk after BI, the abdominal aorta in OZR had narrowed 8.3% ± 1.1% relative to baseline compared with an expansion of 2.4% ± 2.2% in LZR. Simultaneously, the thoracic aorta had expanded 9.5% ± 4.3% in LZR compared with stenosis of 2.8% ± 1.6% in OZR. Calculation of the intimal:medial thickness ratio revealed significantly increased neointimal formation in the OZR descending aorta compared with that in LNR. In conclusion, this minimally invasive BI model involving the rat descending aorta is compatible with available endovascular instruments. The descending aorta of OZR demonstrates enhanced neointimal formation and constrictive vascular remodeling after BI.