Abstract-Techniques of arterial injury commonly used in animals to mimic endovascular procedures are not suitable for small mouse arteries. This has limited examination of the response to arterial injury in genetically modified mice. We therefore sought to develop a model of transluminal injury to the mouse femoral artery that would be reproducible and result in substantial levels of intimal hyperplasia. Mice of the C57BL/6 strain underwent bilateral femoral artery denudation by passage of an angioplasty guidewire. Intimal hyperplasia was observed in 10% of injured arteries at 1 week, in 88% at 2 weeks, and in 90% at 4 weeks. The mean intimal-to-medial area ratio reached 1.1Ϯ0.1 at 4 weeks. No intimal proliferation was found in control sham-operated arteries. One hour after injury, the denuded surface was covered with platelets and leukocytes, predominantly neutrophils. This was associated with the accumulation of P-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1. Expression of these adhesion molecules was not seen in the underlying medial smooth muscle cells. At 24 hours, few neutrophils remained on the denuded surface. At 1 week, macrophages and platelets were present in the vessel wall, partially covered by regenerated endothelium. Transluminal wire injury to the mouse femoral artery induces abundant intimal hyperplasia formation by 2 and 4 weeks and elicits the rapid accumulation of leukocytes and adhesion molecules on the denuded luminal surface. This model will be a valuable tool to study arterial injury in genetically modified mouse models.
Background-HDL cholesterol levels are inversely correlated with coronary heart disease risk in humans, and in animal studies, HDL elevation decreases formation and progression of foam-cell lesions. The potential for HDL to affect preexisting advanced atherosclerotic lesions is not known. To approach this issue, we used a novel mouse aortic transplantation model. Methods and Results-ApoE-deficient (EKO) mice were fed a Western-type diet for 6 months, and thoracic aortic segments containing advanced lesions replaced segments of the abdominal aorta of 4-month-old EKO syngeneic mice not expressing (plasma HDL cholesterol Ϸ26 mg/dL) or expressing (HDL Ϸ64 mg/dL) a human apoAI (hAI) transgene. Immunostaining for CD68 and other macrophage-associated proteins, monocyte chemoattractant protein-1, acyl coenzyme A:cholesterol acyltransferase, and tissue factor, in lesions of pretransplant and EKO recipient mice showed abundant macrophages. In contrast, compared with any other group, lesional macrophage area in hAI/EKO mice decreased Ͼ80% (PϽ0.003), and smooth muscle cell content (␣-actin staining) increased Ͼ300% (PϽ0.006). The decrease in macrophages and increase in smooth muscle cells was primarily in the superficial subendothelial layer. Conclusions-Increasing HDL cholesterol levels in EKO mice retards progression of advanced atherosclerotic lesions and remodels them to a more stable
More than 50% of all cancer patients receive some form of radiotherapy for tumor control preoperatively, postoperatively, or as sole treatment. Radiation-induced wounds are a concern for patients and practitioners. Current research investigating alternative treatment strategies offers the hope of improved wound healing and enhanced quality of life for patients with these wounds. This paper reviews the pathophysiology of wounds following radiation treatment, the methods for treating radiation-induced wounds, and experimental treatment strategies that have been investigated.
Nearly complete regression of advanced atherosclerotic lesions can be achieved with sustained normalization of the plasma lipoprotein profile. Syngeneic arterial transplantation in mice is a novel and valuable model system for atherosclerosis research; and magnetic resonance imaging can detect differences in characteristics in lesions undergoing regression.
Abstract-Monocyte chemoattractant protein (MCP)-1 is upregulated in atherosclerotic plaques and in the media and intima of injured arteries. CC chemokine receptor 2 (CCR2) is the only known functional receptor for MCP-1. Mice deficient in MCP-1 or CCR2 have marked reductions in atherosclerosis. This study examines the effect of CCR2 deficiency in a murine model of femoral arterial injury. Four weeks after injury, arteries from CCR2 Ϫ/Ϫ mice showed a 61.4% reduction (PϽ0.01) in intimal area and a 62% reduction (PϽ0.05) in intima/media ratio when compared with CCR2 ϩ/ϩ littermates. The response of CCR2 ϩ/Ϫ mice was not significantly different from that of CCR2 ϩ/ϩ mice. Five days after injury, the medial proliferation index, determined by bromodeoxyuridine incorporation, was decreased by 59.8% in CCR2 Ϫ/Ϫ mice when compared with CCR2 ϩ/ϩ littermates (PϽ0.05). Although leukocytes rapidly adhered to the injured arterial surface, there was no significant macrophage infiltration in the arterial wall of either CCR2 Ϫ/Ϫ or CCR2 ϩ/ϩ mice 5 and 28 days after injury. These results demonstrate that CCR2 plays an important role in mediating smooth muscle cell proliferation and intimal hyperplasia in a non-hyperlipidemic model of acute arterial injury. CCR2 may thus be an important target for inhibiting the response to acute arterial injury. . MCP-1 antigen is not detected in normal vascular endothelium, but is found on the luminal endothelium of early human atherosclerotic lesions. 2 MCP-1 expression is induced in medial SMCs during early atherosclerotic lesion development in carotid arteries of non-human primates fed a hypercholesterolemic diet. 3 In advanced human atherosclerotic plaques, MCP-1 is expressed in macrophages and SMCs. 2,4,5 MCP-1 antigen and mRNA are also induced in medial SMCs in animal models of arterial injury. 6 -8
Platelet integrin ␣IIb3 (GPIIb/IIIa) plays a central role in the initiation of arterial thrombosis, but its contribution to disseminated microvascular thrombosis is less well defined. Therefore, wild-type mice (3 ؉/؉ ), 3-integrin-deficient mice (3 ؊/؊ ), and wild-type mice treated with a hamster monoclonal antibody (1B5) that blocks murine ␣IIb3 function were tested in models of large-vessel and microvascular thrombosis. In the large-vessel model, ferric chloride was used to injure the carotid artery, and the time to thrombosis was measured. In 3 ؉/؉ mice, the median time to occlusion was 6.7 minutes, whereas occlusion did not occur in any of the 3 ؊/؊ mice tested (P < .001). Fab and F(ab') 2 fragments of 1B5 increased the median time to occlusion. To initiate systemic intravascular thrombosis, prothrombotic agents were administered intravenously, and platelet thrombus formation was monitored by the decrease in circulating platelet count. Three minutes after the injection of adenosine diphosphate (ADP), collagen ؉ epinephrine, or tissue factor, the platelet counts in 3 ؉/؉ mice decreased by 289, 424, and 429 ؋ 10 3 /L, respectively. 3 ؊/؊ mice and wild-type mice pretreated with 1B5 Fab (1 mg/kg, IP) were nearly completely protected from the effects of ADP. In contrast, 3 ؊/؊ mice were only partially protected from the effects of collagen ؉ epinephrine and minimally protected from the effects of tissue factor. In all cases, less fibrin became deposited in the lungs of 3 ؊/؊ mice than in wild-type mice. These results suggest that though ␣IIb3 plays a dominant role in large-vessel thrombosis, it plays a variable role in systemic intravascular thrombosis. (Blood. 2001;98: 1055-1062)
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.