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 (Fgfr1/2Flk1-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 Fgfr1/2Flk1-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 injuryinduced 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.choroidal neovascularization | oxygen-induced retinopathy | retinopathy of prematurity | neoangiogenesis N eovascularization is critical for tissue repair and pathological conditions, including aberrant ocular angiogenesis and cancer (1-4). Although FGF signaling has been prominently implicated in these processes based on genetic inactivation experiments in mice and in vitro studies, the functional in vivo requirement of this pathway in the endothelial cell (EC) vs. other vascular cell types is not known (5-8).The FGF family is composed of 18 signaling ligands, which interact with four cell surface tyrosine kinase receptors. FGF receptor (FGFR) signaling regulates many biological processes, including survival, differentiation, proliferation, and angiogenesis through the activation of RAS-RAF-MAPK, PI3K, STAT, and PLC gamma pathways (6, 9). The EC response to FGF signals is well described in in vitro models of angiogenesis (10, 11). Moreover, previous gene expression analysis showed that Fgfr1 and Fgfr2 were the predominant Fgfrs in ECs (5), whereas Fgfr3 was sparsely detected (12, 13) and Fgfr4 expression was not reported (8). To this end, and given the critical role of FGFRs 1 and 2 during embryonic development, we tested the hypothesis that EC FGFR1/2 may play a key role during vascular development, homeostasis, and response to injury.Studies aimed at understanding the functional requirement of vascular FGF signaling have demonstrated a critical role in homeostasis and angiogenesis (14-16). In these studies, in vivo expression of an adenoviral-based soluble FGF trap (sFGFR) or a dominant inhibitor of all FGFRs (FGF...

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Blocking the FGF/FGFR system as a ⿿two-compartment⿿ antiangiogenic/antitumor approach in cancer therapy

“…Experiments performed on FGFR1 and FGFR2 null mice in both endothelial and hematopoietic cells indicate that these receptors are not required for vascular homeostasis or physiological functions. However, FGFR signalling in endothelial cells plays a pivotal role in tissue repair and neovascularization following injury, pointing to endothelial cell FGFRs as a target for the therapy of diseases characterized by an aberrant vascular proliferation [41].…”

Fibroblast Growth Factor Signaling in the Vasculature

“…Systemic administration of soluble dominant negative FGFR1 decreased VEGFR2 expression and impaired post-ischemic neovascularization. Recently, studies with endothelial and hematopoietic-specific deletion of Fgfr1 and Fgfr2 revealed that Fgfr1 and Fgfr2 are dispensable for normal vascular development; however, loss of endothelial Fgfr1 and Fgfr2 results in impaired neovascularization after injury in adult mice [49••]. In addition, studies using a new allosteric FGFR inhibitor, SSR128129E, showed in a zebrafish model of vascular development that FGF signaling regulates angiogenic sprouting of the intersomitic vessels (ISV) [69•].…”