Hypoxia up‐regulates the angiogenic cytokine secretoneurinviaan HIF‐1α‐ and basic FGF‐dependent pathway in muscle cells

Abstract

Expression of angiogenic cytokines like vascular endothelial growth factor is enhanced by hypoxia. We tested the hypothesis that decreased oxygen levels up-regulate the angiogenic factor secretoneurin. In vivo, muscle cells of mouse ischemic hind limbs showed increased secretoneurin expression, and inhibition of secretoneurin by a neutralizing antibody impaired the angiogenic response in this ischemia model. In a mouse soft tissue model of hypoxia, secretoneurin was increased in subcutaneous muscle fibers. In vitro, secretoneurin mRNA and protein were up-regulated in L6 myoblast cells after exposure to low oxygen levels. The hypoxia-dependent regulation of secretoneurin was tissue specific and was not observed in endothelial cells, vascular smooth muscle cells, or AtT20 pituitary tumor cells. The hypoxia-dependent induction of secretoneurin in L6 myoblasts is regulated by hypoxia-inducible factor-1alpha, since inhibition of this factor using si-RNA inhibited up-regulation of secretoneurin. Induction of secretoneurin by hypoxia was dependent on basic fibroblast growth factor in vivo and in vitro, and inhibition of this regulation by heparinase suggests an involvement of low-affinity basic fibroblast growth factor binding sites. In summary, our data show that the angiogenic cytokine secretoneurin is up-regulated by hypoxia in muscle cells by hypoxia-inducible factor-1alpha- and basic fibroblast growth factor-dependent mechanisms.

Gene Therapy With the Angiogenic Cytokine Secretoneurin Induces Therapeutic Angiogenesis by a Nitric Oxide–Dependent Mechanism

“…We also could show that SN is upregulated in skeletal muscle cells by hypoxia via an indirect, b-FGF-and hypoxia-inducible factor 1-␣-dependent pathway. 17 In this work, we also demonstrated that inhibition of SN worsened the physiological angiogenic response in the hindlimb ischemia model. Recently, a beneficial effect of SN was reported in murine stroke models, resulting in antiapoptotic effects of SN on neuronal cells mediated by the Jak/Stat pathway, resulting from effects on stem cells and induction of angiogenesis.…”

Pro-hormone Secretogranin II Regulates Dense Core Secretory Granule Biogenesis in Catecholaminergic Cells

“…Although this secretory protein has been extensively used as a marker of the regulated secretory pathway (53,57,58), its function in the formation of DCGs has not been carefully investigated, and so far it remains elusive (19,22). By analyzing the consequences of SgII down-regulation in the neuroendocrine PC12 cell line, and its ability to rescue a regulated secretory pathway in the secretory-deficient PC12 variant A35C, we demonstrate the importance of SgII for DCG biogenesis in neuroendocrine cells and characterize fundamental features of SgIImediated granulogenesis.…”

“…Evidence gathered so far reports the formation of granule-like structures in the fibroblast-like COS-1 cell line (19), and a vesicular distribution of secretoneurin immunoreactivity in ischemic mouse muscle fibers (22). Common genetic variation at the human SCG2 locus modulates SgII transcriptional expression, which correlates with blood pressure elevation (2).…”

Distribution of TRAP‐positive cells and expression of HIF‐1α, VEGF, and FGF‐2 in the reparative reaction in patients with osteonecrosis of the femoral head

“…Several studies have demonstrated that hypoxia up-regulates HIF-1a, VEGF, and FGF-2 expression in tissue and shows positive correlation with the tissue repair process. 15,27,28 In normal and transformed cell lines, HIF-1a has been identified as the master regulator of the transcriptional response to oxygen deprivation, 29 and regulates the expression of numerous target genes that control angiogenesis, including VEGF.…”