Thrombospondin-1 (TSP1) can inhibit angiogenesis by interacting with endothelial cell CD36 or proteoglycan receptors. We have now identified ␣31 integrin as an additional receptor for TSP1 that modulates angiogenesis and the in vitro behavior of endothelial cells. Recognition of TSP1 and an ␣31 integrin-binding peptide from TSP1 by normal endothelial cells is induced after loss of cell-cell contact or ligation of CD98. Although confluent endothelial cells do not spread on a TSP1 substrate, ␣31 integrin mediates efficient spreading on TSP1 substrates of endothelial cells deprived of cell-cell contact or vascular endothelial cadherin signaling. Activation of this integrin is independent of proliferation, but ligation of the ␣31 integrin modulates endothelial cell proliferation. In solution, both intact TSP1 and the ␣31 integrin-binding peptide from TSP1 inhibit proliferation of sparse endothelial cell cultures independent of their CD36 expression. However, TSP1 or the same peptide immobilized on the substratum promotes their proliferation. The TSP1 peptide, when added in solution, specifically inhibits endothelial cell migration and inhibits angiogenesis in the chick chorioallantoic membrane, whereas a fragment of TSP1 containing this sequence stimulates angiogenesis. Therefore, recognition of immobilized TSP1 by ␣31 integrin may stimulate endothelial cell proliferation and angiogenesis. Peptides that inhibit this interaction are a novel class of angiogenesis inhibitors. INTRODUCTIONAngiogenesis under normal and pathological conditions is regulated by both positive and negative signals received from soluble growth factors and components of the extracellular matrix (reviewed by Folkman, 1995;Polverini, 1995;Hanahan and Folkman, 1996). Thrombospondins are a family of extracellular matrix proteins that have diverse effects on cell adhesion, motility, proliferation, and survival (reviewed by Bornstein, 1992Bornstein, , 1995Roberts, 1996). Two members of this family, thrombospondin-1 (TSP1) and thrombospondin-2, are inhibitors of angiogenesis (Good et al., 1990;Volpert et al., 1995). TSP1 inhibits growth, sprouting, and motility responses of endothelial cells in vitro (Good et al., 1990;Taraboletti et al., 1990;Iruela Arispe et al., 1991;Canfield and Schor, 1995;Tolsma et al., 1997) and, under defined conditions, induces programmed cell death in endothelial cells (Guo et al., 1997b). TSP1 inhibits angiogenesis in vivo in the rat corneal pocket and chick chorioallantoic membrane (CAM) angiogenesis assays (Good et al., 1990;Iruela-Arispe et al., 1999). The ability of TSP1 overexpression to suppress tumor growth and neovascularization in several tumor xenograft models provides further evidence for an antiangiogenic activity of TSP1 (Dameron et al., 1994;Weinstat-Saslow et al., 1994;Sheibani and Frazier, 1995;Hsu et al., 1996). Circulating TSP1 may also inhibit neovascularization of micrometastases in some cancers (Morelli et al., 1998;Volpert et al., 1998). A few studies, however, have concluded that TSP1 also has p...
The GATA-6 transcription factor is expressed in cardiogenic cells and during subsequent stages of heart development in diverse vertebrate species. To gain insights into the molecular events that govern this heartrestricted expression, we isolated the chicken GATA-6 gene and used several approaches to screen for associated control regions. Our analysis of two chicken GATA-6/lacZ constructs in transgenic mouse embryos was particularly revealing. One GATA-6/lacZ construct, which has 1.5 kilobase pairs of upstream sequences along with the promoter and first intron, was expressed exclusively in the atrioventricular canal region of the heart. This expression pattern is novel and appears to mark specialized myocardial cells that induce underlying endocardial cells to initiate valve formation. The other GATA-6/ lacZ construct, which has an additional 7.7 kilobase pairs of upstream sequences, was expressed in the ventricle and outflow tract in addition to the atrioventricular canal. The failure of these GATA-6 control regions to function as enhancers in transfected cardiac myocyte cultures underscores the importance of using transgenic approaches to elucidate transcriptional controls that function in the developing heart. Although the endogenous GATA-6 gene is expressed throughout the heart, our results indicate that this is effected in a heart region-specific manner.Although commitment to the cardiogenic lineage and the events that precede cardiac myocyte differentiation are still poorly understood at the transcriptional level, major advances have recently been made in understanding the roles that various growth factors serve in this context. In particular, members of the transforming growth factor- family of growth factors have been shown to effect the specification of precardiac mesoderm, whereas members of the fibroblast growth factor family of growth factors have been shown to regulate the subsequent proliferation and differentiation of these committed cells (1, 2). The genes that are regulated in direct response to these extracellular signals and the transcription factors that mediate these programming events within the cardiogenic lineage have not yet been elucidated.The transcriptional controls that function within terminally differentiated cardiac myocytes have been analyzed in much greater detail owing to the relative ease of obtaining material for study. Transient transfection and direct muscle injection assays have been used to map control regions for many cardiac genes (for review, see Refs. 3 and 4), and some of these control regions have also been shown to direct heart-restricted expression in transgenic mice. Several of these control regions derive from genes that are expressed in a heart region-specific manner, and in general, the respective control regions have been found to function in a similar manner in transgenic animals. Examples include the ventricular control region from the mouse ventricular MLC-2v gene (5) and the atrial control region from the quail atrial slow MyHC3 gene (6). Since many card...
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