Objective— Vascular endothelial growth factor (VEGF) plays critical roles in the regulation of angiogenesis and lymphangiogenesis. However, tissue edema, hemorrhage, and inflammation occur when VEGF-A is used for angiogenic therapy. To design a novel angiogenic factor without severe side effects, we examined the biological function of chimeric VEGF-E NZ7 /placental growth factor (PlGF), which is composed of Orf-Virus NZ7 -derived VEGF-E NZ7 and human PlGF1, in a transgenic (Tg) mouse model. Methods and Results— A strong angiogenic response was observed in both VEGF-E NZ7 /PlGF and VEGF-A 165 Tg mice. Notably, the vascular leakage of VEGF-E NZ7 /PlGF-induced blood vessels was 4-fold lower than that of VEGF-A 165 –induced blood vessels. Furthermore, the monocyte/macrophage recruitment in the skin of VEGF-E NZ7 /PlGF Tg mice was &8-fold decreased compared with that of VEGF-A 165 Tg mice. In addition, the lymphatic vessels in VEGF-E NZ7 /PlGF Tg mice were structurally normal, whereas they were markedly dilated in VEGF-A 165 Tg mice, possibly because of the high vascular leakage. Receptor binding assay demonstrated that VEGF-E NZ7 /PlGF was the ligand only activating VEGF receptor (VEGFR)-2. Conclusion— These results indicated that neither the hyperpermeability in response to simultaneous stimulation of VEGFR-1 and VEGFR-2 nor VEGFR-1–mediated severe inflammation was associated with VEGF-E NZ7 /PlGF-induced angiogenesis. The unique receptor binding property may shed light on VEGF-E NZ7 /PlGF as a novel candidate for therapeutic angiogenesis.

We cloned the Schizosaccharomyces pombe map1 gene by virtue of its ability to stimulate transcription of the sxa2 gene, which encodes a carboxypeptidase expressed specifically in h ؊ cells in response to mating-pheromone signaling. The cloned gene had a coding capacity of 398 amino acids split by two introns, and the deduced product was a protein of the MADS box family. This gene was most similar to Saccharomyces cerevisiae MCM1, which regulates cell-type-specific gene expression in budding yeast cells. Disruption of the S. pombe gene did not affect vegetative cell growth but conferred sterility. It blocked the mating ability of h ؉ cells completely and that of h ؊ cells partially. Genetic and sequencing analysis indicated that the cloned gene is map1, which was originally defined by a mutation that caused h ؉ -specific sterility. Northern (RNA) blot analysis showed that the function of map1 is absolutely essential for the expression of h ؉ -specific genes and is required for the full activation of h ؊ -specific gene expression. Overexpression of map1 resulted in enhanced transcription of cell-type-specific genes, but the range of genes affected by Map1 was restricted by the mating type of the cell. Results of yeast two-hybrid analysis suggested that Map1 may physically interact with Mat1-Pc, the product of the h ؉ -specific mating-type gene mat1-Pc. On the basis of these observations, we speculate that Map1 may be a transcriptional regulator of cell-type-specific genes similar to S. cerevisiae MCM1, whose activity is modulated by the ␣1 and ␣2 mating-type gene products.Cells of the fission yeast Schizosaccharomyces pombe initiate sexual development when starved for nutrients, especially a nitrogen source. Haploid cells of the opposite mating types, termed h ϩ (P) and h Ϫ (M), communicate by secreting mating pheromones prior to mating: h ϩ cells produce P-factor and the M-factor receptor, while h Ϫ cells produce M-factor and the P-factor receptor, in response to nutritional starvation (17, 37). This cell-type-specific production of pheromones and receptors is observed only upon nutrient deprivation. Indeed, neither diploid-nor haploid-specific gene expression during mitotic growth in S. pombe has been reported.The mating-pheromone response pathway of S. pombe provides a model system for the study of signal transduction in eukaryotic cells. This pathway involves a receptor-coupled Gprotein system (33, 49, 64) and a mitogen-activated protein (MAP) kinase cascade (18,44,46,65,67). Mutants of S. pombe that exhibit sterility in a mating-type-specific manner have been useful in the identification of factors required for pheromonal communication. Four h ϩ -specific sterility genes, named map1 through map4, and four h Ϫ -specific sterility genes, named mam1 through mam4, have been identified (11, 26, 27a, 65). The map2 gene encodes a precursor of P-factor, in which four repeats of the mature P-factor sequence are embedded (26). The gene products of map3 and mam2 are both putative seven-transmembrane proteins. Genetic e...