Endothelial cell FGF signaling is required for injury response but not for vascular homeostasis

Sunday S. Oladipupo, Craig Smith, Andrea Santeford, Changwon Park, Abdoulaye Sene, Luke A. Wiley, Patrick Osei-Owusu, Joann Hsu, Nicole Zapata, Fang Liu, Rei Nakamura, Kory J. Lavine, Kendall J. Blumer, Kyunghee Choi, Rajendra S. Apte, David M. Ornitz

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

Endothelial cells (ECs) express fibroblast growth factor receptors (FGFRs) and are exquisitely sensitive to FGF signals. However, whether the EC or another vascular cell type requires FGF signaling during development, homeostasis, and response to injury is not known. Here, we show that Flk1-Cre or Tie2-Cre mediated deletion of FGFR1 and FGFR2 (Fgfr1/2Flk1-Creor Fgfr1/2Tie2-Cremice), which results in deletion in endothelial and hema-topoietic cells, is compatible with normal embryonic development. As adults, Fgfr1/2Flk1-Cremice maintain normal blood pressure and vascular reactivity and integrity under homeostatic conditions. However, neovascularization after skin or eye injury was significantly impaired in both Fgfr1/2Flk1-Creand Fgfr1/2Tie2-Cremice, independent of either hematopoietic cell loss of FGFR1/2 or vascular endothelial growth factor receptor 2 (Vegfr2) haploinsuf-ficiency. Also, impaired neovascularization was associated with delayed cutaneous wound healing. These findings reveal a key requirement for cell-autonomous EC FGFR signaling in injury-induced angiogenesis, but not for vascular homeostasis, identifying the EC FGFR signaling pathway as a target for diseases associated with aberrant vascular proliferation, such as age-related macular degeneration, and for modulating wound healing without the potential toxicity associated with direct manipulation of systemic FGF or VEGF activity.

Original languageEnglish
Pages (from-to)13379-13384
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number37
DOIs
StatePublished - Sep 16 2014

Keywords

  • Choroidal neovascularization
  • Neoangiogenesis
  • Oxygen-induced retinopathy
  • Retinopathy of prematurity

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