We have shown previously that vascular endothelial growth factor (VEGF) synthesized by the cellular constituents of small vessels per se, viz. endothelial cells and pericytes, participates in the hypoxia-driven proliferation of both cell types (Nomura, M., Yamagishi, S.,

Induction of pluripotent stem cells from human fibroblasts has been achieved by the ectopic expression of two different sets of four genes. However, the mechanism of the pluripotent stem cell induction has not been elucidated. Here we identified a marked heterogeneity in colonies generated by the four-gene (Oct3/4, Sox2, c-Myc, and Klf4) transduction method in human neonatal skin-derived cells. The four-gene transduction gave a higher probability of induction for archetypal pluripotent stem cell marker genes (Nanog, TDGF, and Dnmt3b) than for marker genes that are less specific for pluripotent stem cells (CYP26A1 and TERT) in primary induction culture. This tendency may reflect the molecular mechanism underlying the induction of human skin-derived cells into pluripotent stem cells. Among the colonies induced by the four-gene transduction, small cells with a high nucleus-to-cytoplasm ratio could be established by repeated cloning. Subsequently established cell lines were similar to human embryonic stem cells as well as human induced pluripotent stem (iPS) cells derived from adult tissue in morphology, gene expression, long-term self-renewal ability, and teratoma formation. Genome-wide single-nucleotide polymorphism array analysis of the human iPS cell line indicates that the induction process did not induce DNA mutation.

Rev-erbK K and retinoic acid receptor-related orphan receptor-K K (RORK K) are orphan nuclear receptors but their effects on transcription are opposed. Here, we show that Rev-erbK K was expressed predominantly in vascular smooth muscle cells (VSMCs) rather than endothelial cells. Overexpression of Rev-erbK K upregulated the expression of interleukin-6 and cyclooxygenase-2, and increased transactivation by NF-U UB and translocation of p65 to the nucleus in A7r5 VSMCs. Furthermore, the expression of Rev-erbK K was upregulated by RORK K1 but that upregulation was attenuated by Rev-erbK K itself in A7r5 VSMCs. These results suggest a regulatory link between ReverbK K and the NF-U UB pathway.

Retinoic acid receptor-related orphan receptor-K K (RORK K) is a nuclear orphan receptor. Adenovirus-mediated overexpression of RORK K1 and RORK K4 suppressed tumor necrosis factor-K K (TNF-K K)-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) in human umbilical vein endothelial cells. Overexpression of RORK K1 and RORK K4 also suppressed TNF-K K-stimulated translocation of p50 and p65 to the nucleus. In contrast, dominant-negative deletion mutants of RORK K1 and RORK K4 failed to suppress the induction of VCAM-1 and ICAM-1 and translocations of p50 and p65. These results suggest that RORK K1 and RORK K4 regulate the in£ammatory responses via inhibition of the nuclear factor-U UB signaling pathway in endothelial cells.

This study concerns whether advanced glycation endproducts (AGE) are related to microvascular derangement in diabetes, exemplified by pericyte loss and angiogenesis in retinopathy and by mesangial expansion in nephropathy. AGE caused a decrease in viable pericytes cultivated from bovine retina. On the other hand, AGE stimulated the growth and tube formation of human microvascular endothelial cells (EC), this being mediated by autocrine vascular endothelial growth factor. In AGE‐exposed rat mesangial cells, type IV collagen synthesis was induced. Those AGE actions were dependent on a cell surface receptor for AGE (RAGE), because they were abolished by RAGE antisense or ribozyme. The AGE‐RAGE system may thus participate in the development of diabetic microangiopathy. This proposition was supported by experiments with animal models; several indices characteristic of retinopathy were correlated with circulating AGE levels in OLETF rats. The predisposition to nephropathy was augmented in RAGE transgenic mice when they became diabetic.