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This Article Full Text Full Text (PDF) All Versions of this Article: 290/6/L1183    most recent 00175.2005v1 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 Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Majka, S. Articles by Izzo, A. Search for Related Content PubMed PubMed Citation Articles by Majka, S. Articles by Izzo, A.

Pleiotropic role of VEGF-A in regulating fetal pulmonary mesenchymal cell turnover

¹Department of Medicine, Cardiovascular Pulmonary Research Section, Divisions of ²Cardiology and ³Pulmonary Sciences and Critical Care Medicine, and ⁴Denver Veterans Administration Medical Center, University of Colorado Health Sciences Center, Denver, Colorado; ⁵Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico; and ⁶Department of Microbiology, Immunology & Pathology, Colorado State University, Fort Collins, Colorado

Submitted 19 April 2005 ; accepted in final form 9 January 2006

Tight regulation of VEGF-A production and signaling is important for the maintenance of lung development and homeostasis. VEGF null mice have provided little insight into the role of VEGF during the later stages of lung morphogenesis. Therefore, we examined the in vitro effects of autocrine and paracrine VEGF-A production and the inhibition of VEGF-A signaling on a Flk-1-negative subset of fetal pulmonary mesenchymal cells (pMC). We hypothesized that VEGF-A receptor signaling regulates turnover of fetal lung mesenchyme in a cell cycle-dependent manner. VEGF receptor blockade with SU-5416 caused cell spreading and decreased proliferation and bcl-2 localization. Nuclear expression of the cell cycle inhibitory protein, p21, was increased with SU-5416 treatment, and p27 was absent. Autocrine VEGF production by pMC resulted in proliferation and p21/p27-dependent contact inhibition. In contrast, exogenous VEGF-A increased cell progression through the cell cycle. Selective activation of Flt by placental growth factor demonstrated the importance of this receptor/kinase in the VEGF-A responsiveness of pMC. The expression and localization of the survival factor bcl-2 was dependent on VEGF. These results provide evidence that VEGF-A plays a critical role in the regulation of fetal pulmonary mesenchymal proliferation, survival, and the subsequent development of normal lung architecture through bcl-2 and p21/p27-dependent cell cycle control.

proliferation; bronchopulmonary dysplasia; SUGEN 5416

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