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

SS Oladipupo, C Smith, A Santeford… - Proceedings of the …, 2014 - National Acad Sciences
SS Oladipupo, C Smith, A Santeford, C Park, A Sene, LA Wiley, P Osei-Owusu, J Hsu…
Proceedings of the National Academy of Sciences, 2014National Acad Sciences
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 …
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-Cre or Fgfr1/2Tie2-Cre mice), which results in deletion in endothelial and hematopoietic cells, is compatible with normal embryonic development. As adults, Fgfr1/2Flk1-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 Fgfr1/2Flk1-Cre and Fgfr1/2Tie2-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.
National Acad Sciences