RGD-Conjugated Human Ferritin Nanoparticles for Imaging Vascular Inflammation and Angiogenesis in Experimental Carotid and Aortic Disease
MOLECULAR IMAGING AND BIOLOGY
2012; 14 (3): 315-324
Bioluminescence and Magnetic Resonance Imaging of Macrophage Homing to Experimental Abdominal Aortic Aneurysms
2012; 11 (2): 126-134
Inflammation and angiogenesis are important contributors to vascular disease. We evaluated imaging both of these biological processes, using Arg-Gly-Asp (RGD)-conjugated human ferritin nanoparticles (HFn), in experimental carotid and abdominal aortic aneurysm (AAA) disease.Macrophage-rich carotid lesions were induced by ligation in hyperlipidemic and diabetic FVB mice (n?=?16). AAAs were induced by angiotensin II infusion in apoE(-/-) mice (n=10). HFn, with or without RGD peptide, was labeled with Cy5.5 and injected intravenously for near-infrared fluorescence imaging.RGD-HFn showed significantly higher signal than HFn in diseased carotids and AAAs relative to non-diseased regions, both in situ (carotid: 1.88?±?0.30 vs. 1.17?±?0.10, p?=?0.04; AAA: 2.59?±?0.24 vs. 1.82?±?0.16, p?=?0.03) and ex vivo. Histology showed RGD-HFn colocalized with macrophages in carotids and both macrophages and neoangiogenesis in AAA lesions.RGD-HFn enhances vascular molecular imaging by targeting both vascular inflammation and angiogenesis, and allows more comprehensive detection of high-risk atherosclerotic and aneurysmal vascular diseases.
View details for DOI 10.1007/s11307-011-0495-1
View details for Web of Science ID 000303884400006
View details for PubMedID 21638084
Hyperglycemia limits experimental aortic aneurysm progression
JOURNAL OF VASCULAR SURGERY
2010; 52 (4): 975-983
Macrophage infiltration is a prominent feature of abdominal aortic aneurysm (AAA) progression. We used a combined imaging approach with bioluminescence (BLI) and magnetic resonance imaging (MRI) to study macrophage homing and accumulation in experimental AAA disease. Murine AAAs were created via intra-aortic infusion of porcine pancreatic elastase. Mice were imaged over 14 days after injection of prepared peritoneal macrophages. For BLI, macrophages were from transgenic mice expressing luciferase. For MRI, macrophages were labeled with iron oxide particles. Macrophage accumulation during aneurysm progression was observed by in situ BLI and by in vivo 7T MRI. Mice were sacrificed after imaging for histologic analysis. In situ BLI (n ?=? 32) demonstrated high signal in the AAA by days 7 and 14, which correlated significantly with macrophage number and aortic diameter. In vivo 7T MRI (n ?=? 13) at day 14 demonstrated T?* signal loss in the AAA and not in sham mice. Immunohistochemistry and Prussian blue staining confirmed the presence of injected macrophages in the AAA. BLI and MRI provide complementary approaches to track macrophage homing and accumulation in experimental AAAs. Similar dual imaging strategies may aid the study of AAA biology and the evaluation of novel therapies.
View details for DOI 10.2310/7290.2011.00033
View details for Web of Science ID 000307645900004
View details for PubMedID 22469240
Hyperglycemia modulates plasminogen activator inhibitor-1 expression and aortic diameter in experimental aortic aneurysm disease
2010; 148 (2): 429-435
Diabetes mellitus (DM) is associated with reduced progression of abdominal aortic aneurysm (AAA) disease. Mechanisms responsible for this negative association remain unknown. We created AAAs in hyperglycemic mice to examine the influence of serum glucose concentration on experimental aneurysm progression.Aortic aneurysms were induced in hyperglycemic (DM) and normoglycemic models by using intra-aortic porcine pancreatic elastase (PPE) infusion in C57BL/6 mice or by systemic infusion of angiotensin II (ANG) in apolipoprotein E-deficient (ApoE(-/-)) mice, respectively. In an additional DM cohort, insulin therapy was initiated after aneurysm induction. Aneurysmal aortic enlargement progression was monitored with serial transabdominal ultrasound measurements. At sacrifice, AAA cellularity and proteolytic activity were evaluated by immunohistochemistry and substrate zymography, respectively. Influences of serum glucose levels on macrophage migration were examined in separate models of thioglycollate-induced murine peritonitis.At 14 days after PPE infusion, AAA enlargement in hyperglycemic mice (serum glucose ? 300 mg/dL) was less than that in euglycemic mice (PPE-DM: 54% ± 19% vs PPE: 84% ± 24%, P < .0001). PPE-DM mice also demonstrated reduced aortic mural macrophage infiltration (145 ± 87 vs 253 ± 119 cells/cross-sectional area, P = .0325), elastolysis (% residual elastin: 20% ± 7% vs 12% ± 6%, P = .0209), and neovascularization (12 ± 8 vs 20 ± 6 vessels/high powered field, P = .0229) compared with PPE mice. Hyperglycemia limited AAA enlargement after ANG infusion in ApoE(-/-) mice (ANG-DM: 38% ± 12% vs ANG: 61% ± 37% at day 28). Peritoneal macrophage production was reduced in response to thioglycollate stimulation in hyperglycemic mice, with limited augmentation noted in response to vascular endothelial growth factor administration. Insulin therapy reduced serum glucose levels and was associated with AAA enlargement rates intermediate between euglycemic and hyperglycemic mice (PPE: 1.21 ± 0.14 mm vs PPE-DM: 1.00 ± 0.04 mm vs PPE-DM + insulin: 1.14 ± 0.05 mm).Hyperglycemia reduces progression of experimental AAA disease; lowering of serum glucose levels with insulin treatment diminishes this protective effect. Identifying mechanisms of hyperglycemic aneurysm inhibition may accelerate development of novel clinical therapies for AAA disease.
View details for DOI 10.1016/j.jvs.2010.05.086
View details for Web of Science ID 000282660300023
View details for PubMedID 20678880
Hemodynamic Influences on abdominal aortic aneurysm disease: Application of biomechanics to aneurysm pathophysiology
2010; 53 (1-2): 11-21
Extracellular matrix degradation is a sentinel pathologic feature of abdominal aortic aneurysm (AAA) disease. Diabetes mellitus, a negative risk factor for AAA, may impair aneurysm progression through its influence on the fibrinolytic system. We hypothesize that hyperglycemia limits AAA progression through effects on endogenous plasminogen activator inhibitor-1 (PAI-1) levels and subsequent reductions in plasmin generation.Experimental AAAs were induced in diabetic and control mice via the intra-aortic elastase infusion method. Serial transabdominal high-frequency ultrasound examinations were performed to monitor aortic diameter following elastase infusion. Circulating PAI-1 and plasmin alpha2-antiplasmin (PAP) complex concentrations were determined by ELISA and local expression of PAI-1 levels was examined by RT-PCR and immunohistochemistry.Hyperglycemia was associated with reduced AAA diameter, increased plasma PAI-1 concentration and reduced plasmin generation. Aneurysmal aortic PAI-1 gene expression increased in parallel with plasma concentration, with peak expression occurring early after aneurysm initiation.Hyperglycemia increases PAI-1 expression and attenuates AAA diameter in experimental AAA disease. These results emphasize the role of the fibrinolytic pathway in AAA pathophysiology, and suggest a candidate mechanism for hyperglycemic inhibition of AAA disease.
View details for DOI 10.1016/j.surg.2010.05.014
View details for Web of Science ID 000280433200034
View details for PubMedID 20561659
Identifying abdominal aortic aneurysm risk factors in postmenopausal women.
Women's health (London, England)
2009; 5 (1): 33-37
"Atherosclerotic" abdominal aortic aneurysms (AAAs) occur with the greatest frequency in the distal aorta. The unique hemodynamic environment of this area predisposes it to site-specific degenerative changes. In this review, we summarize the differential hemodynamic influences present along the length of the abdominal aorta, and demonstrate how alterations in aortic flow and wall shear stress modify AAA progression in experimental models. Improved understanding of aortic hemodynamic risk profiles provides an opportunity to modify patient activity patterns to minimize the risk of aneurysmal degeneration.
View details for DOI 10.1016/j.vph.2010.03.004
View details for Web of Science ID 000278450300002
View details for PubMedID 20347049
Evaluation of: Lederle FA, Larson JC, Margolis KL et al.: Abdominal aortic aneurysm events in the Women's Health Initiative: cohort study. Br. Med. J. 337, A1724 (2008). A linked cohort study of 161,808 postmenopausal women aged 50-79 years enrolled in the Women's Health Initiative was conducted during which participants were followed for the incidence of abdominal aortic aneurysm repair or rupture. This study evaluated the association between potential risk factors and subsequent abdominal aortic aneurysm events in women. A total of 467 women reported a diagnosis of abdominal aortic aneurysm before entering the study or during participation, with 184 aneurysm-related events identified. Abdominal aortic aneurysm events were strongly associated with age and smoking and negatively associated with diabetes and baseline use of postmenopausal hormone supplementation. Previous studies investigating abdominal aortic aneurysm have focused primarily on men, with little reliable information available on women. This study contributes a large female cohort to provide better insight into gender-specific abdominal aortic aneurysm risks and disease associations.
View details for DOI 10.2217/17455057.5.1.33
View details for PubMedID 19102638