TY - JOUR
T1 - Endothelial cell FGF signaling is required for injury response but not for vascular homeostasis
AU - Oladipupo, Sunday S.
AU - Smith, Craig
AU - Santeford, Andrea
AU - Park, Changwon
AU - Sene, Abdoulaye
AU - Wiley, Luke A.
AU - Osei-Owusu, Patrick
AU - Hsu, Joann
AU - Zapata, Nicole
AU - Liu, Fang
AU - Nakamura, Rei
AU - Lavine, Kory J.
AU - Blumer, Kendall J.
AU - Choi, Kyunghee
AU - Apte, Rajendra S.
AU - Ornitz, David M.
PY - 2014/9/16
Y1 - 2014/9/16
N2 - 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.
AB - 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.
KW - Choroidal neovascularization
KW - Neoangiogenesis
KW - Oxygen-induced retinopathy
KW - Retinopathy of prematurity
UR - http://www.scopus.com/inward/record.url?scp=84907215716&partnerID=8YFLogxK
U2 - 10.1073/pnas.1324235111
DO - 10.1073/pnas.1324235111
M3 - Article
C2 - 25139991
AN - SCOPUS:84907215716
SN - 0027-8424
VL - 111
SP - 13379
EP - 13384
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 37
ER -