mural cell associated vegf is required for organotypic vessel formation壁画organotypic所需细胞vegf相关血管的形成.pdfVIP

Mural Cell Associated VEGF Is Required for Organotypic Vessel Formation 1 1¤a 1 1 1 Lasse Evensen , David R. Micklem , Anna Blois , Sissel Vik Berge , Niels Aarsæther , Amanda 2 2¤b 1 Littlewood-Evans , Jeanette Wood , James B. Lorens * 1 Department of Biomedicine, University of Bergen, Bergen, Norway, 2 Oncology Research, Novartis Institutes for BioMedical Research, Basel, Switzerland Abstract Background: Blood vessels comprise endothelial cells, mural cells (pericytes/vascular smooth muscle cells) and basement membrane. During angiogenesis, mural cells are recruited to sprouting endothelial cells and define a stabilizing context, comprising cell-cell contacts, secreted growth factors and extracellular matrix components, that drives vessel maturation and resistance to anti-angiogenic therapeutics. Methods and Findings: To better understand the basis for mural cell regulation of angiogenesis, we conducted high content imaging analysis on a microtiter plate format in vitro organotypic blood vessel system comprising primary human endothelial cells co-cultured with primary human mural cells. We show that endothelial cells co-cultured with mural cells undergo an extensive series of phenotypic changes reflective of several facets of blood vessel formation and maturation: Loss of cell proliferation, pathfinding-like cell migration, branching morphogenesis, basement membrane extracellular matrix protein deposition, lumen formation, anastamosis and development of a stabilized capillary-like network. This phenotypic sequence required endothelial-mural cell-cell contact, mural