Abstract-Angiopoietin-1 (Ang1) has powerful vascular protective effects: suppressing plasma leakage, inhibiting vascular inflammation, and preventing endothelial death. Preclinical studies indicate that Ang1 may be therapeutically useful in a number of situations, including treatment of edema, endotoxemia, and transplant arteriosclerosis. However, the ligand has also been implicated in vessel remodeling, induction of angiogenesis and pulmonary hypertension, indicating that strategies to minimize any deleterious effects while optimizing vessel protection are likely to be needed. This review surveys the published data on vascular protective effects of Ang1 and highlights the therapeutic potential of this ligand, as well as possible limitations to its use. We also consider the data on Ang1 receptors and speculate on how to maximize therapeutic benefit by targeting the Tie receptors.
BACKGROUND: Symptomatic carotid disease due to thromboembolism has been associated with acute plaque instability and intraplaque haemorrhage. These features may be influenced by the fragility and position of plaque neovessels. The purpose of this study was, therefore, to determine whether any association existed between neovessel density, position, morphology and thromboembolic sequelae. METHODS: Carotid endarterectomy (CEA) samples were collected from 15 asymptomatic patients with greater than 80 per cent stenosis and from 13 patients with greater than 80 per cent stenosis and symptoms within 30 days of CEA. Groups were matched for sex, age, risk factors and plaque size. Samples were stained with haematoxylin and eosin, and Van Gieson stains. An endothelial-specific antibody to CD31 was used for immunohistochemistry. Plaques were assessed for histological characteristics while neovessels were counted and characterized by size, site and shape. RESULTS: There were more neovessels in plaques (P < 0.00001) and fibrous caps (P < 0.0001) from symptomatic than asymptomatic patients. Symptomatic plaque neovessels were larger in size (P< 0.004) and more irregular in shape. There was a significant increase in plaque necrosis and rupture in symptomatic plaques. Plaque haemorrhage and rupture were associated with more neovessels within the plaque (P < 0.02, P < 0. 001) and fibrous cap (P < 0.05, P < 0.004). Patients with preoperative or intraoperative embolization had more plaque and fibrous cap neovessels (P < 0.03, P < 0.001). CONCLUSION: Symptomatic carotid disease is associated with increased neovascularization within the atherosclerotic plaque and fibrous cap; these vessels appear larger in size, more irregular in shape and may contribute to plaque instability and onset of thromboembolic events.
The Tie1 receptor tyrosine kinase was isolated over a decade ago, but so far no ligand has been found to activate this receptor. Here, we have examined the potential of angiopoietins, ligands for the related Tie2 receptor, to mediate Tie1 activation. We show that a soluble Ang1 chimeric protein, COMP-Ang1, stimulates Tie1 phosphorylation in endothelial cells with similar kinetics and angiopoietin dose dependence when compared with Tie2. The phosphorylation of overexpressed Tie1 was weakly induced by COMP-Ang1 also in transfected cells that do not express Tie2. When cotransfected, Tie2 formed heteromeric complexes with Tie1, enhanced Tie1 activation, and induced phosphorylation of a kinase-inactive Tie1 in a ligand-dependent manner. Tie1 phosphorylation was also induced by native Ang1 and Ang4, although less efficiently than with COMP-Ang1. In conclusion, we show that Tie1 phosphorylation is induced by multiple angiopoietin proteins and that the activation is amplified via Tie2. These results should be important in dissecting the signal transduction pathways and biological functions of Tie1.
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