title: Endothelial cell FGF signaling is required for injury response but not for vascular homeostasis.
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.
authors.affiliation: Departments of Developmental Biology.
authors.forename: Sunday S
authors.initials: SS
authors.lastname: Oladipupo
authors.affiliation: Departments of Developmental Biology.
authors.forename: Craig
authors.initials: C
authors.lastname: Smith
authors.affiliation: Ophthalmology and Visual Sciences.
authors.forename: Andrea
authors.initials: A
authors.lastname: Santeford
authors.affiliation: Pathology and Immunology.
authors.forename: Changwon
authors.initials: C
authors.lastname: Park
authors.affiliation: Ophthalmology and Visual Sciences.
authors.forename: Abdoulaye
authors.initials: A
authors.lastname: Sene
authors.affiliation: Ophthalmology and Visual Sciences.
authors.forename: Luke A
authors.initials: LA
authors.lastname: Wiley
authors.affiliation: Cell Biology and Physiology, and.
authors.forename: Patrick
authors.initials: P
authors.lastname: Osei-Owusu
authors.affiliation: Departments of Developmental Biology.
authors.forename: Joann
authors.initials: J
authors.lastname: Hsu
authors.affiliation: Ophthalmology and Visual Sciences.
authors.forename: Nicole
authors.initials: N
authors.lastname: Zapata
authors.affiliation: Pathology and Immunology.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Ophthalmology and Visual Sciences.
authors.forename: Rei
authors.initials: R
authors.lastname: Nakamura
authors.affiliation: Departments of Developmental Biology, Medicine, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Kory J
authors.initials: KJ
authors.lastname: Lavine
authors.affiliation: Cell Biology and Physiology, and.
authors.forename: Kendall J
authors.initials: KJ
authors.lastname: Blumer
authors.affiliation: Pathology and Immunology.
authors.forename: Kyunghee
authors.initials: K
authors.lastname: Choi
authors.affiliation: Departments of Developmental Biology, Ophthalmology and Visual Sciences, apte@vision.wustl.edu dornitz@wustl.edu.
authors.forename: Rajendra S
authors.initials: RS
authors.lastname: Apte
authors.affiliation: Departments of Developmental Biology, apte@vision.wustl.edu dornitz@wustl.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: Ornitz
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001808:Blood Vessels / Q000473:pathology*; D002199:Capillary Permeability; D042783:Endothelial Cells / Q000378:metabolism*; D004789:Enzyme Activation; D005123:Eye / Q000473:pathology; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006410:Hematopoiesis; D006706:Homeostasis; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology; D019426:Integrases / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D013312:Stress, Physiological; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014945:Wound Healing
chemical_list: D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors; D040301:Vascular Endothelial Growth Factor Receptor-2; C045073:Cre recombinase; D019426:Integrases
keywords: choroidal neovascularization; neoangiogenesis; oxygen-induced retinopathy; retinopathy of prematurity