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      Caveolin-1 Orchestrates Fibroblast Growth Factor 2 Signaling Control of Angiogenesis in Placental Artery Endothelial Cell Caveolae

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          Abstract

          Fibroblast growth factor (FGF) receptor 1 (FGFR1) protein was expressed as the long and short as well as some truncated forms in ovine fetoplacental artery ex vivo and in vitro. Upon FGF2 stimulation, both the long and short FGFR1s were tyrosine phosphorylated and the PI3K/AKT1 and ERK1/2 pathways were activated in a concentration- and time- dependent manner in ovine fetoplacental artery endothelial (oFPAE) cells. Blockade of the PI3K/AKT1 pathway attenuated FGF2-stimulated cell proliferation and migration as well as tube formation; blockade of the ERK1/2 pathway abolished FGF2-stimulated tube formation and partially inhibited cell proliferation and did not alter cell migration. Both AKT1 and ERK1/2 were co-fractionated with caveolin-1 and activated by FGF2 in the caveolae. Disruption of caveolae by methyl-β-cyclodextrin inhibited FGF2 activation of AKT1 and ERK1/2. FGFR1 was found in the caveolae where it physically binds to caveolin-1. FGF2 stimulated dissociation of FGFR1 from caveolin-1. Downregulation of caveolin-1 significantly attenuated the FGF2-induced activation of AKT1 and ERK1/2 and inhibited FGF2-induced cell proliferation, migration and tube formation in oFPAE cells. Pretreatment with a caveolin-1 scaffolding domain peptide to mimic caveolin-1 overexpression also inhibited these FGF2-induced angiogenic responses. These data demonstrate that caveolae function as a platform for regulating FGF2-induced angiogenesis through spatiotemporally compartmentalizing FGFR1 and the AKT1 and ERK1/2 signaling modules; the major caveolar structural protein caveolin-1 interacts with FGFR1 and paradoxically regulates FGF2-induced activation of PI3K/AKT1 and ERK1/2 pathways that coordinately regulate placental angiogenesis.

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          Author and article information

          Journal
          0050222
          4586
          J Cell Physiol
          Journal of Cellular Physiology
          0021-9541
          1097-4652
          16 August 2011
          June 2012
          1 June 2013
          : 227
          : 6
          : 2480-2491
          Affiliations
          [1 ]Department of Obstetrics & Gynecology University of California Irvine, Irvine, CA 92697
          [2 ]Department of Obstetrics & Gynecology, University of Wisconsin-Madison, Madison, WI 53715.
          Author notes
          Address correspondence to: Dong-bao Chen, Ph.D., Department of Obstetrics and Gynecology, University of California Irvine, Irvine, CA 92697. Tel: 949-824-2409; dongbaoc@ 123456uci.edu
          Article
          PMC3248968 PMC3248968 3248968 nihpa318326
          10.1002/jcp.22984
          3248968
          21830216
          ecaa9590-5106-4dbe-8aa8-ba878c5f29ce
          Funding
          Funded by: National Heart, Lung, and Blood Institute : NHLBI
          Award ID: R21 HL098746-01A1 || HL
          Funded by: National Heart, Lung, and Blood Institute : NHLBI
          Award ID: R01 HL074947-05 || HL
          Funded by: National Heart, Lung, and Blood Institute : NHLBI
          Award ID: R01 HL070562-08 || HL
          Categories
          Article

          cell signaling,FGF2,caveolin-1,caveolae,endothelial cells,placenta

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