Tissue components, including EC, skeletal muscles, and myeloid cells, regulate the angiogenic process ( 9, 13). Thus, up-regulated Glrx inhibits angiogenic pathways ( 12).Д«ecause previous studies used global transgenic or knockout mice, we explored the tissue-specific role of Glrx and its regulation of protein S-glutathionylation. Consistent with these findings, increased protein S-glutathionylation by Glrx deletion promotes mouse ischemic limb revascularization after femoral artery ligation ( 11). We further demonstrated that S-glutathionylation of cysteine in the oxygen-dependent degradation domain of hypoxia-inducible factor (HIF)-1О± stabilizes HIF-1О± and increases angiogenic factors ( 11). Increased S-glutathionylation also inhibits Ras-related C3 botulinum toxin substrate (Rac)1, a small Rho GTPase, and promotes EC permeability ( 10), an initial step for EC migration. As a consequence, overexpression of Glrx inhibits in vitro EC migration and in vivo ischemic limb revascularization in global Glrx transgenic mice ( 9). The formation of a GSH adduct on the cysteine-674 of sarco/endoplasmic reticulum calcium ATPase activates the Ca 2+ pump and promotes EC migration ( 7, 8). Protein S-glutathionylation can regulate angiogenesis through several target proteins. Endothelial cell (EC) migration is an essential component of angiogenesis, which is required for many physiologic and pathologic processes, including wound healing, tissue regeneration, and tumor growth ( 6). Therefore, Glrx is a crucial molecule for redox signaling regulated by the protein S-glutathionylation.ДЄngiogenesis is the process of forming new blood vessels from preexisting ones.

De-glutathionylation (removal of GSH adducts) can occur spontaneously but is more efficiently driven by the catalyzing enzyme glutaredoxin-1 (Glrx) ( 4). Protein S-glutathionylation can regulate a variety of cellular processes, including transcription, apoptosis, and cytoskeletal assembly ( 4, 5). Oxidants promote protein S-glutathionylation, which is a reversible post-translational modification of protein cysteine residues with the tripeptide glutathione (GSH). Oxidants, or reactive oxygen and nitrogen species, have been recognized to play an essential role in signal transduction ( 1 вЂ“ 3). Endothelial cell-specific redox gene modulation inhibits angiogenesis but promotes B16F0 tumor growth in mice. D., Watanabe, Y., Tsukahara, Y., Ferran, B., Murdoch, C. These data suggest that impaired ischemic vascularization does not necessarily associate with suppression of tumor growth, and that antiangiogenic therapies may be ineffective for melanoma tumors because of their ability to implement vasculogenic mimicry during hypoxia.-Yura, Y., Chong, B.

EC-Glrx TG mice showed higher levels of VEGF-A in the tumors, indicating hypoxia, which may stimulate tumor cells to form vascular channels without EC, referred to as vasculogenic mimicry. Despite reduced angiogenesis, EC-Glrx TG mice unexpectedly developed larger tumors compared with control mice. Additionally, ECs migrated less into subcutaneously implanted B16F0 melanoma tumors as assessed by decreased staining of EC markers. EC-specific Glrx transgenic (EC-Glrx TG) overexpression in mice significantly impaired EC migration in Matrigel implants and hind limb revascularization after femoral artery ligation. Here, we examined the role of EC-specific Glrx up-regulation in distinct models of angiogenesis namely, hind limb ischemia and tumor angiogenesis.

Although Glrx up-regulation prevented endothelial cell (EC) migration and global Glrx transgenic mice had impaired ischemic vascularization, the effects of cell-specific Glrx overexpression remained unknown. Glutaredoxin-1 (Glrx) is a small cytosolic enzyme that removes S-glutathionylation, glutathione adducts of protein cysteine residues, thus modulating redox signaling and gene transcription.

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