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Blood, 22 October 2009, Vol. 114, No. 17, pp. 3707-3716. Prepublished online as a Blood First Edition Paper on August 25, 2009; DOI 10.1182/blood-2008-12-195750. This Article Full Text Full Text (PDF) Supplemental Methods, Tables, and Figures Additional Supplemental Figures and Supplemental Videos All Versions of this Article: blood-2008-12-195750v1 114/17/3707    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Yamamizu, K. Articles by Yamashita, J. K. PubMed PubMed Citation Articles by Yamamizu, K. Articles by Yamashita, J. K. Related Collections Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  VASCULAR BIOLOGY Enhancement of vascular progenitor potential by protein kinase A through dual induction of Flk-1 and Neuropilin-1 Kohei Yamamizu1, Kyoko Kawasaki2, Shiori Katayama1, Tetsuro Watabe2, and Jun K. Yamashita1,3 1 Laboratory of Stem Cell Differentiation, Stem Cell Research Center, Institute for Frontier Medical Sciences, Kyoto University, Kyoto; 2 Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo; and 3 Center for iPS Cell Research and Application, Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto, Japan Fine tuning of vascular endothelial growth factor (VEGF) signaling is critical in endothelial cell (EC) differentiation and vascular development. Nevertheless, the system for regulating the sensitivity of VEGF signaling has remained unclear. Previously, we established an embryonic stem cell culture reproducing early vascular development using Flk1 (VEGF receptor-2)+ cells as common progenitors, and demonstrated that cyclic adenosine monophosphate (cAMP) enhanced VEGF-induced EC differentiation. Here we show that protein kinase A (PKA) regulates sensitivity of Flk1+ vascular progenitors to VEGF signaling for efficient EC differentiation. Blockade of PKA perturbed EC differentiation and vascular formation in vitro and ex vivo. Overexpression of constitutive active form of PKA (CA-PKA) potently induced EC differentiation and vascular formation. Expression of Flk1 and Neuropilin-1 (NRP1), which form a selective and sensitive receptor for VEGF165, was increased only in CA-PKA–expressing progenitors, enhancing the sensitivity of the progenitors to VEGF165 by more than 10 times. PKA activation induced the formation of a VEGF165, Flk1, and NRP1 protein complex in vascular progenitors. These data indicate that PKA regulates differentiation potential of vascular progenitors to be endothelial competent via the dual induction of Flk1 and NRP1. This new-mode mechanism regulating "progenitor sensitivity" would provide a novel understanding in vascular development and regeneration. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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