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Proc Natl Acad Sci U S A. 2014 Sep 16;111(37):13379-84. doi: 10.1073/pnas.1324235111. Epub 2014 Aug 19.

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

Author information

  • 1Departments of Developmental Biology.
  • 2Ophthalmology and Visual Sciences.
  • 3Pathology and Immunology.
  • 4Cell Biology and Physiology, and.
  • 5Departments of Developmental Biology, Medicine, Washington University School of Medicine, St. Louis, MO 63110.
  • 6Departments of Developmental Biology, Ophthalmology and Visual Sciences, apte@vision.wustl.edu dornitz@wustl.edu.
  • 7Departments of Developmental Biology, apte@vision.wustl.edu dornitz@wustl.edu.

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 (Fgfr1/2(Flk1-Cre) or Fgfr1/2(Tie2-Cre) mice), which results in deletion in endothelial and hematopoietic cells, is compatible with normal embryonic development. As adults, Fgfr1/2(Flk1-Cre) mice maintain normal blood pressure and vascular reactivity and integrity under homeostatic conditions. However, neovascularization after skin or eye injury was significantly impaired in both Fgfr1/2(Flk1-Cre) and Fgfr1/2(Tie2-Cre) mice, independent of either hematopoietic cell loss of FGFR1/2 or vascular endothelial growth factor receptor 2 (Vegfr2) haploinsufficiency. 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.

KEYWORDS:

choroidal neovascularization; neoangiogenesis; oxygen-induced retinopathy; retinopathy of prematurity

PMID:
25139991
[PubMed - indexed for MEDLINE]
PMCID:
PMC4169958
Free PMC Article
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