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Nitric oxide (NO) has been suggested to be a pathophysiological modulator of cell proliferation, cell cycle arrest, and apoptosis. In this context, NO can exert opposite effects under diverse conditions. Indeed, several studies have indicated that low relative concentrations of NO seem to favor cell proliferation and antiapoptotic responses and higher levels of NO favor pathways inducing cell cycle arrest, mitochondria respiration, senescence, or apoptosis. Here we report the effects of NO on both promotion and inhibition of cell proliferation, in particular in regard to cardiovascular disease, diabetes, and stem cells. Moreover, we focus on molecular mechanisms of action involved in the control of cell cycle progression, which include both cyclic guanosine monophosphate-dependent and -independent pathways. This growing field may lead to broad and novel targeted therapies against cardiovascular diseases, especially concomitant type 2 diabetes, as well as novel bioimaging NO-based diagnostic tools.

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Tumor growth requires neoangiogenesis. VEGF is the most potent proangiogenic factor. Dysregulation of hypoxia-inducible factor (HIF) or cytokine stimuli such as those involving the chemokine receptor 4/stromal-derived cell factor 1 (CXCR4/SDF-1) axis are the major cause of ectopic overexpression of VEGF in tumors. Although the CXCR4/SDF-1 pathway is well characterized, the transcription factors executing the effector function of this signaling are poorly understood. The multifunctional Yin Yang 1 (YY1) protein is highly expressed in different types of cancers and may regulate some cancer-related genes. The network involving CXCR4/ YY1 and neoangiogenesis could play a major role in cancer progression. In this study we have shown that YY1 forms an active complex with HIF-1α at VEGF gene promoters and increases VEGF transcription and expression observed by RT-PCR, ELISA, and Western blot using two different antibodies against VEGFB. Long-term treatment with T22 peptide (a CXCR4/SDF-1 inhibitor) and YY1 silencing can reduce in vivo systemic neoangiogenesis (P < 0.01 and P < 0.05 vs. control, respectively) during metastasis. Moreover, using an in vitro angiogenesis assay, we observed that YY1 silencing led to a 60% reduction in branches (P < 0.01) and tube length (P < 0.02) and a 75% reduction in tube area (P < 0.001) compared with control cells. A similar reduction was observed using T22 peptide. We demonstrated that T22 peptide determines YY1 cytoplasmic accumulation by reducing its phosphorylation via downregulation of AKT, identifying a crosstalk mechanism involving CXCR4/YY1. Thus, YY1 may represent a crucial molecular target for antiangiogenic therapy during cancer progression.cancer | metastasis | oncogene A ngiogenesis is critical to the growth, invasion, and metastasis of human tumors (1, 2). Because targeting angiogenesis has emerged as a promising strategy for the therapeutic treatment of cancer, understanding the transcriptional regulation that determines the tumor angiogenic phenotype has become of cardinal importance (3).Yin Yang 1 (YY1) protein has diverse roles in cancer development (4) including drug resistance (5, 6) and transcriptional regulation of many genes (7). YY1 also is involved in the regulation of angiogenesis during malignancy (8). Certainly, YY1 silencing reduced intrametastatic and systemic neoangiogenesis interacting with the chemokine receptor 4 (CXCR4) pathway in osteosarcoma (SaOS) cells (8). Interestingly, CXCR4 is required for cancer progression and blood supply via neoangiogenesis (9-11). Accordingly, some of CXCR4 inhibitors are being evaluated in clinical trials as adjunct therapy (12) (http://clinicaltrials.gov). The network that involves CXCR4/YY1 and neoangiogenesis could play a major role in cancer pathobiology. In this study, we demonstrate that YY1 has a crucial role during neoangiogenesis and elucidate the mechanism by which CXCR4/YY1 inhibition reduces VEGF-dependent neoangiogenesis. ResultsEffects of YY1 Silencing and CXCR4 Inhibition on Angiogenesis. To monitor angiog...