Abstract-The major arteries and veins of the vertebrate circulatory system are formed early in embryonic development, before the onset of circulation, following de novo aggregation of "angioblast" progenitors in a process called vasculogenesis. Initial embryonic determination of artery or vein identity is regulated by variety of genetic factors that work in concert to specify endothelial cell fate, giving rise to 2 distinct components of the circulatory loop possessing unique structural characteristics. Work in multiple in vivo animal model systems has led to a detailed examination of the interacting partners that determine arterial and venous specification. We discuss the hierarchical arrangement of many signaling molecules, including Hedgehog (Hh), vascular endothelial growth factor (VEGF), Notch, and chicken ovalbumin upstream-transcription factor II (COUP-TFII) that promote or inhibit divergent pathways of endothelial cell fate. Elucidation of the functional role of these genetic determinants of blood vessel specification together with the epigenetic factors involved in subsequent modification of arterial-venous identity will allow for potential new therapeutic targets for vascular disorders. (Circ Res. 2009;104:576-588.)

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Fibroblast growth factor-binding protein (FGF-BP) 1 is a secreted protein that can bind fibroblast growth factors (FGFs) 1 and 2. These FGFs are typically stored on heparan sulfate proteoglycans in the extracellular matrix in an inactive form, and it has been proposed that FGF-BP1 functions as a chaperone molecule that can mobilize locally stored FGF and present the growth factor to its tyrosine kinase receptor. FGF-BP1 is upregulated in squamous cell, colon, and breast cancers and can act as an angiogenic switch during malignant progression of epithelial cells. For the present studies, we focused on FGF-1 and -2 and investigated interactions with recombinant human FGF-BP1 protein as well as effects on signal transduction, cell proliferation, and angiogenesis. We show that recombinant FGF-BP1 specifically binds FGF-2 and that this binding is inhibited by FGF-1, heparan sulfate, and heparinoids. Furthermore, FGF-BP1 enhances FGF-1-and FGF-2-dependent proliferation of NIH-3T3 fibroblasts and FGF-2-induced extracellular signal-regulated kinase 2 phosphorylation. Finally, in the chicken chorioallantoic membrane angiogenesis assay, FGF-BP1 synergizes with exogenously added FGF-2. We conclude that FGF-BP1 binds directly to FGF-1 and FGF-2 and positively modulates the biological activities of these growth factors. Fibroblast growth factors (FGFs)1 represent a family of over 20 distinct proteins that are widely expressed in various tissues. FGFs have been reported to be involved in both development and adult tissue homeostasis, as well as in angiogenesis and cancer progression. FGF-2 (basic FGF), a 16 -18-kDa protein, is one of the best-studied members of this family and has been shown to have a variety of biological effects in different cells and organ systems, including embryonic development, tumorigenesis, and angiogenesis (for a review, see Refs. 1 and 2).FGF-2 interacts with low affinity cell surface and extracellular matrix heparan sulfate proteoglycans, which enable the growth factor to bind and activate its high affinity tyrosine kinase receptors (FGFRs), thereby forming a trimolecular active complex (3-6). It has been reported that cell surface heparan sulfate proteoglycans can modulate the action of FGF-2 by increasing its affinity for FGFRs (7). Moreover, heparan sulfate proteoglycans seem to protect FGF-2 from degradation by proteases in the extracellular environment (8, 9) and modulate the bioavailability of FGF-2, generating a local reservoir for the growth factor (10). The binding of FGF-2 to the cell surface receptor induces receptor tyrosine kinase dimerization and autophosphorylation (11). The phosphorylated FGFRs associate and subsequently activate SH2 domain-containing downstream signaling molecules, such as phospholipase C␥ (12, 13) and Src (14,15). Moreover, upon ligand-dependent receptor autophosphorylation, adaptor proteins, such as Grb2 and Shc, link the FGFRs to the Ras/MAPK signaling cascade (16 -18). Grb2 and Shc form a complex with the GDP/GTP exchange factor Son of Sevenless (Sos), which ...