It has been shown that increase in plasma homocysteine (Hcy) impairs P5091 vascular endothelium and correlates with the development of atherosclerosis. However, the effect of hyperhomocysteinemia (HHcy) on the formation of cerebral aneurysm remains unknown. Methods: Male Sprague-Dawley rats examined for developing cerebral aneurysms after surgical induction in the presence and absence of hypercysteinemia induced by a high L-methionine diet (1 g/kg/d). Aneurysms

developed at the anterior cerebral-olfactory artery bifurcation were classified as 4 stages from no abnormality to saccular aneurysm. Plasma homocysteine levels and expression of vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), SB431542 mw matrix metalloproteinase-2 (MMP-2), and MMP-9 in aneurysmal walls was examined and correlated with CA formation 3 months after surgery. Results: Methionine diet significantly increased plasma homocysteine levels, accelerates CA formation after ligation of the left common carotid artery. Expression of VEGF, iNOS, MMP-2, and MMP-9 in aneurysmal walls was also increased

by methionine treatment. Conclusion: Hyperhomocysteinemia accelerates cerebral aneurysm formation, potentially through differential effects on expression of molecules critical for vascular wall modeling in a rat model. (C) 2011 Elsevier Ireland Ltd. All rights reserved.”
“Hantavirus pulmonary syndrome Bcl-w (HPS) and hemorrhagic

fever with renal syndrome (HFRS) are severe diseases associated with hantavirus infection. High levels of virus replication occur in microvascular endothelial cells but without a virus-induced cytopathic effect. However, virus infection results in microvascular leakage, which is the hallmark of these diseases. VE-cadherin is a major component of adherens junctions, and its interaction with the vascular endothelial growth factor (VEGF) receptor, VEGF-R2, is important for maintaining the integrity of the endothelial barrier. Here we report that increased secreted VEGF and concomitant decreased VE-cadherin are seen at early times postinfection of human primary lung endothelial cells with an HPS-associated hantavirus, Andes virus. Furthermore, active virus replication results in increased permeability and loss of the integrity of the endothelial cell barrier. VEGF binding to VEGF-R2 is known to result in dissociation of VEGF-R2 from VE-cadherin and in VE-cadherin activation, internalization, and degradation. Consistent with this, we showed that an antibody which blocks VEGF-R2 activation resulted in inhibition of the Andes virus-induced VE-cadherin reduction. These data implicate virus induction of VEGF and reduction in VE-cadherin in the endothelial cell permeability seen in HPS and suggest potential immunotherapeutic targets for the treatment of the disease.