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WIREs Syst Biol Med
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Role of fibroblast growth factor signaling in vascular formation and maintenance: orchestrating signaling networks as an integrated system

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Abstract The vascular system has begun to be perceived as a dynamic organ actively controlling a wide variety of physiological processes. The structural and functional integrity of blood vessels, regulated by signaling activities finely modulating cell–cell and cell–matrix interactions, is crucial for vessel physiology, as well as basic functionality of the tissue. Throughout the process of new vessel formation, while blood vessels are actively reorganized and remodeled with migration and proliferation of vascular cells, maintenance of vascular barrier function is essentially important. These conflicting properties, i.e., dynamic cellular mobilization and maintenance of barrier integrity, are simultaneously achieved through the interaction of highly organized signaling networks governing coordinated cell–cell interplay. Recent evidence suggests that the fibroblast growth factor (FGF) system plays a regulatory role in several physiological conditions in the vascular system. In this article, we will attempt to summarize current knowledge in order to understand the mechanism of this coordination and evaluate the pivotal role of FGF signaling in integrating a diverse range of signaling events in vascular growth and maintenance. WIREs Syst Biol Med 2012, 4:615–629. DOI: 10.1002/wsbm.1190 This article is categorized under: Biological Mechanisms > Cell Signaling Physiology > Mammalian Physiology in Health and Disease Biological Mechanisms > Regulatory Biology

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Fibroblast growth factor (FGF) signal transduction pathways. Dimerization of FGFR results in the phosphorylation of FGFR substrate 2 (FRS2). A signaling complex with growth factor receptor‐bound 2 (Grb2), Geb2‐associated binding protein 1 (Gab1), and Src homology (SH) 2‐domain containing tyrosine phosphate 2 (Shp2) bind to phosphorylated FRS2. The recruitment of Son of sevenless (Sos) to the plasma membrane by Grb2 and Shp2 leads to the activation of Ras and Raf, which results in downstream MAPK (Erk1/2, p38, JNK) activation. Phosphoinositide 3‐kinase (PI3K) binds to Gab1 and phosphorylates phosphatidylinositol‐4,5‐bisphosphate (PIP2) to generate phosphatidylinositol‐3,4,5‐tryphosphate (PIP3). PIP3 activates the Akt pathway. Phospholipase C gamma (PLC‐γ) binds to FGFR and produces diacylglycerol (DAG) and inositol 1,4,5‐triphosphate (IP3) by PIP2 hydrolysis. The IP3 causes the release of Ca2+ that activates protein kinase C (PKC). DAG is also required for PKC activation. Activated PKC activates Raf and other various substrates in the PKC pathway.

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Pleiotropic action of fibroblast growth factor (FGF) signaling in new vessel formation. FGF regulates different aspects of vessel formation via controlling multiple growth factor signaling. FGF signaling may be able to selectively upregulate VEGFR2 expression in the tip cell of the sprouting vessel, thereby increasing the sensitivity of the tip cell responding to VEGF and projecting cellular extension. At the vessel maturation stage, pericytes invest nascent blood vessels, responding to PDGF‐BB expressed by endothelial cells, which may also be stimulated by FGF signaling. Whereas, a strong FGF signaling in endothelial cells with concomitant VEGFR2 upregulation promotes the mobilization of endothelial tip cells required for triggering angiogenesis, in the later vessel maturation stage, basal FGF signaling, which is not sufficient to increase VEGF signaling, stabilizes newly formed vessels by promoting the formation of VE‐cadherin‐based adherens junctions and endothelial survival. The endothelial–pericyte adhesion mediated by N‐cadherin can also be regulated by FGF signaling via FGFR's capability to interact with N‐cadherin.

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Coordination of vascular growth factors by fibroblast growth factor (FGF). Endothelial FGF signaling upregulates VEGFR2 expression, thereby increasing endothelial sensitivity to VEGF and promoting angiogenesis. FGF signaling also potentiates PDGF‐induced vascular maturation via FGF‐stimulated expression of PDGFR in mural cells. Moreover, FGF stimulates MCP‐1 synthesis, which, in turn, recruits monocytes to drive vascular formation. Endothelial FGF signaling is also required for the maintenance of blood vessels via stabilizing VE‐cadherin at endothelial cell–cell junctions.

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Biological Mechanisms > Regulatory Biology
Biological Mechanisms > Cell Signaling
Physiology > Mammalian Physiology in Health and Disease

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