Regulation of neovascularization by S-glutathionylation via the Wnt5a/sFlt-1 pathway.
S-glutathionylation occurs when reactive oxygen or nitrogen species react with protein-cysteine thiols. Glutaredoxin-1 (Glrx) is a cytosolic enzyme which enzymatically catalyses the reduction in S-glutathionylation, conferring reversible signalling function to proteins with redox-sensitive thiols. Glrx can regulate vascular hypertrophy and inflammation by regulating the activity of nuclear factor κB (NF-κB) and actin polymerization. Vascular endothelial growth factor (VEGF)-induced endothelial cell (EC) migration is inhibited by Glrx overexpression. In mice overexpressing Glrx, blood flow recovery, exercise function and capillary density were significantly attenuated after hindlimb ischaemia (HLI). Wnt5a and soluble Fms-like tyrosine kinase-1 (sFlt-1) were enhanced in the ischaemic-limb muscle and plasma respectively from Glrx transgenic (TG) mice. A Wnt5a/sFlt-1 pathway had been described in myeloid cells controlling retinal blood vessel development. Interestingly, a Wnt5a/sFlt-1 pathway was found also to play a role in EC to inhibit network formation. S-glutathionylation of NF-κB components inhibits its activation. Up-regulated Glrx stimulated the Wnt5a/sFlt-1 pathway through enhancing NF-κB signalling. These studies show a novel role for Glrx in post-ischaemic neovascularization, which could define a potential target for therapy of impaired angiogenesis in pathological conditions including diabetes.
*Vascular Medicine Section, Aston Medical School Aston University, Aston Triangle, Birmingham B47 ET, U.K.
Colin E
CE
Murdoch
†Vascular Biology Section, Boston University Medical School, Boston, MA 02118, U.S.A.
Markus M
MM
Bachschmid
†Vascular Biology Section, Boston University Medical School, Boston, MA 02118, U.S.A.
Reiko
R
Matsui
D000818:Animals; D054477:Glutaredoxins / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D000071818:Wnt-5a Protein
D054477:Glutaredoxins; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D005978:Glutathione