Human basic fibroblast growth factor (FGF-2) occurs in four isoforms: a low molecular weight (LMW FGF-2, 18 kDa) and three high molecular weight (HMW FGF-2, 22, 22.5, and 24 kDa) forms. LMW FGF-2 is primarily cytoplasmic and functions in an autocrine manner, whereas HMW FGF-2s are nuclear and exert activities through an intracrine, perhaps nuclear, pathway. Selective overexpression of HMW FGF-2 forms in fibroblasts promotes growth in low serum, whereas overexpression of LMW FGF-2 does not. The HMW FGF-2 forms have two functional domains: an amino-terminal extension and a common 18-kDa amino acid sequence. To investigate the role of these regions in the intracrine signaling of HMW FGF-2, we produced stable transfectants of NIH 3T3 fibroblasts overexpressing either individual HMW FGF-2 forms or artificially nucleartargeted LMW FGF-2. All of these forms of FGF-2 localize to the nucleus/nucleolus and induce growth in low serum. The nuclear forms of FGF-2 trigger a mitogenic stimulus under serum starvation conditions and do not specifically protect the cells from apoptosis. These data indicate the existence of a specific role for nuclear FGF-2 and suggest that LMW FGF-2 represents the biological messenger in both the autocrine/paracrine and intracrine FGF-2 pathways. INTRODUCTIONBasic fibroblast growth factor (FGF-2) 1 is a member of a large family of heparin-binding growth factors. Thus far 19 members (Nishimura et al., 1999) have been described. These proteins affect various biological processes ranging from cell proliferation to plasminogen activation, integrin expression, cell migration, embryonic development, and cell differentiation. FGFs also may be involved in tumor angiogenesis and malignant transformation (Burgess and Maciag, 1989;Rifkin and Moscatelli, 1989;Basilico and Moscatelli, 1992;Mason, 1994).The biological functions of the FGFs are mediated by their interaction with both high-and low-affinity plasma membrane receptors (Baird, 1994). A family consisting of four high-affinity tyrosine kinase FGFreceptors has been identified (Basilico and Moscatelli, 1992;Jaye et al., 1992). The interaction of FGF-2 with its plasma membrane high-affinity receptors induces autophosphorylation of the receptor and initiates the phosphorylation of tyrosine residues in cytosolic substrates (Fantl et al., 1993). The low-affinity receptors consist of heparan sulfate proteoglycans and are thought to provide a mechanism both to concentrate ligand and to present FGF dimers to tyrosine kinase receptors Baird, 1994) The prototypic members of the FGF family, FGF-1 and -2, lack a signal sequence for secretion, although the proteins are released and have been visualized in ‡ Corresponding author. E-mail address: aresem01@mcrcr.med. nyu.edu. 1 Abbreviations used: FGF-2, basic fibroblast growth factor; HMW FGF-2, high molecular weight FGF-2; LMW FGF-2, low molecular weight FGF-2.© 1999 by The American Society for Cell Biology 1429 the ECM of different tissues (Abraham et al., 1986;Jaye et al., 1986). The mechanism of FGF-1 and FGF-2 r...

IntroductionImbalance in the network of soluble mediators may play a pivotal role in the pathogenesis of Kaposi's sarcoma (KS).

Unlike other neuronal counterparts, primary synaptic proteins are not known to be involved in vascular physiology. Here, we demonstrate that neurexins and neuroligins, which constitute large and complex families of fundamental players in synaptic activity, are produced and processed by endothelial and vascular smooth muscle cells throughout the vasculature. Moreover, they are dynamically regulated during vessel remodeling and form endogenous complexes in large vessels as well as in the brain. We used the chicken chorioallantoic membrane as a system to pursue functional studies and demonstrate that a monoclonal recombinant antibody against ␤-neurexin inhibits angiogenesis, whereas exogenous neuroligin has a role in promoting angiogenesis. Finally, as an insight into the mechanism of action of ␤-neurexin, we show that the anti-␤-neurexin antibody influences vessel tone in isolated chicken arteries. Our finding strongly supports the idea that even the most complex and plastic events taking place in the nervous system (i.e., synaptic activity) share molecular cues with the vascular system. angiogenesis ͉ vessel tone ͉ cell-to-cell adhesion ͉ nervous-vascular parallels ͉ synapses

Hepatocyte growth factor (HGF) is a powerful motogen and mitogen for epithelial cells. The factor is a 90-kD heterodimer composed of an alpha chain containing four kringle motifs and a beta chain showing structural homologies with serine proteases. It is, however, devoid of enzymatic activity. Recently, it has been reported that HGF activates migration and proliferation of endothelial cells and is angiogenic. In this article we discuss (1) the molecular domains of HGF required to activate in vitro and in vivo endothelial cells, studied by use of molecular mutants, and (2) the characteristics of the angiogenic response to HGF in an experimental model system of implanted reconstituted basement membrane (Matrigel). Two groups of mutants were made and used in vitro and in vivo: one with deletions of kringle domains and one with substitution at the cleavage site of the HGF precursor. In vitro, HGF variants containing only the first two (HGF-NK2) or the first three kringles (HGF-NK3) of the alpha chain did not induce proliferation of endothelial cells even if used at concentration 160-fold higher than that optimal for HGF (0.05 nmol/L). High concentrations of these mutants (4 to 8 nmol/L) activated a little endothelial cell motogenic response that was 60% lower than that elicited by HGF. Substitution of Arg 489 with Gln 489 in the HGF precursor generated an uncleavable single-chain factor, unable to induce either endothelial cell migration or proliferation. In vivo, HGF induced a dose-dependent angiogenic response, which was enhanced by heparin.