<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "The impact of biomechanical forces on the differentiation of vascular cells during arteriogenesis"^^ . "Occlusive vascular diseases represent the most frequent cause of death in industrialized nations. Treatment of the end-stage of these diseases is usually limited to interventions such as angioplasty, bypass surgery or limb amputation. An alternative approach to restore blood flow to the ischemic tissue can be the therapeutic induction of the endogenous collateral circulation (arteriogenesis), bypassing the site of stenosis. Since biomechanical forces have been implicated in the initiation of arteriogenesis, their impact on the remodelling process during the onset of arteriogenesis and on the mechanosensitive expression of a pivotal pro-arteriogenic molecule, monocyte chemoattractant protein-1 (MCP-1), was investigated in the present study. Employing the hindlimb ischemia model and a novel ear artery ligation model revealed that MCP-1 expression is significantly increased in collateral arterioles undergoing arteriogenesis already 24 hours after its onset. To define the mechanism triggering MCP-1 expression, an in situ perfusion model of small mouse arteries was established, mimicking the pro-arteriogenic perfusion conditions. Gene expression analyses showed that MCP-1 expression is predominantly up-regulated in the media of the arterial segments which solely sense changes in circumferential wall strain. Further analyses of cultured endothelial and smooth muscle cells confirmed that elevated levels of shear stress do not up-regulate MCP-1 expression while application of cyclic stretch to both cell types resulted in a robust increase in MCP-1 expression. Inhibition of the mechanosensitive transcription factor activator protein-1 (AP-1) by employing the decoy oligodeoxynucleotide (dODN) technique abolished the stretch-induced MCP-1 expression in the cultured cells as well as in the perfused segments of the mouse mesenteric artery. Further analyses revealed an increased ROS formation in the cultured smooth muscle cells upon exposure to cyclic stretch as well as in the branches of mouse mesenteric artery perfused under pro-arteriogenic flow conditions in situ. Inhibition of ROS production by the ROS scavenger Idebenone abolished stretch-induced MCP-1 expression. Finally, topical application of the AP-1 dODN to the mouse ear after arterial occlusion abrogated remodelling of the collateral arterioles through down-regulating MCP-1 expression and monocyte recruitment. In summary, the data point towards a stretch-induced AP-1 mediated rise in MCP-1 expression in vascular smooth muscle cells as a critical determinant for the initiation of arteriogenesis. Conversely, the present study question the view of arteriogenesis as a predominantly shear stress-mediated remodelling process and contributes to the deeper understanding of a well-orchestrated arterial remodelling process that may eventually be exogenously induced for therapeutic purposes. "^^ . "2008" . . . . . . . . "Elena"^^ . "Demicheva"^^ . "Elena Demicheva"^^ . . . . . . "The impact of biomechanical forces on the differentiation of vascular cells during arteriogenesis (PDF)"^^ . . . "Dissertation_Elena_Demicheva.pdf"^^ . . . "The impact of biomechanical forces on the differentiation of vascular cells during arteriogenesis (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "The impact of biomechanical forces on the differentiation of vascular cells during arteriogenesis (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "The impact of biomechanical forces on the differentiation of vascular cells during arteriogenesis (Other)"^^ . . . . . . "preview.jpg"^^ . . . "The impact of biomechanical forces on the differentiation of vascular cells during arteriogenesis (Other)"^^ . . . . . . "medium.jpg"^^ . . . "The impact of biomechanical forces on the differentiation of vascular cells during arteriogenesis (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #8376 \n\nThe impact of biomechanical forces on the differentiation of vascular cells during arteriogenesis\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .