Redox regulation of ischemic limb neovascularization – What we have learned from animal studies

Abstract

Mouse hindlimb ischemia has been widely used as a model to study peripheral artery disease. Genetic modulation of the enzymatic source of oxidants or components of the antioxidant system reveal that physiological levels of oxidants are essential to promote the process of arteriogenesis and angiogenesis after femoral artery occlusion, although mice with diabetes or atherosclerosis may have higher deleterious levels of oxidants. Therefore, fine control of oxidants is required to stimulate vascularization in the limb muscle. Oxidants transduce cellular signaling through oxidative modifications of redox sensitive cysteine thiols. Of particular importance, the reversible modification with abundant glutathione, called S-glutathionylation (or GSH adducts), is relatively stable and alters protein function including signaling, transcription, and cytoskeletal arrangement. Glutaredoxin-1 (Glrx) is an enzyme which catalyzes reversal of GSH adducts, and does not scavenge oxidants itself. Glrx may control redox signaling under fluctuation of oxidants levels. In ischemic muscle increased GSH adducts through Glrx deletion improves in vivo limb revascularization, indicating endogenous Glrx has anti-angiogenic roles. In accordance, Glrx overexpression attenuates VEGF signaling in vitro and ischemic vascularization in vivo. There are several Glrx targets including HIF-1α which may contribute to inhibition of vascularization by reducing GSH adducts. These animal studies provide a caution that excess antioxidants may be counter-productive for treatment of ischemic limbs, and highlights Glrx as a potential therapeutic target to improve ischemic limb vascularization.

TRPA1 sensitization during diabetic vascular impairment contributes to cold hypersensitivity in a mouse model of painful diabetic peripheral neuropathy

“…These data suggest that diabetic vascular impairment induces TRPA1 sensitization, resulting in cold hypersensitivity in the early phase of DPN. This hypothesis is further supported by the present findings using the hindlimb ischemia model, which has been widely used to study peripheral arterial disease, 56 and is reported to induce cold hypersensitivity. 57 These results suggest that TRPA1 sensitization could be induced by diabetic vascular impairment rather than by other factors, such as metabolic changes or peripheral nerve damage.…”

Cholinergic anti-inflammatory pathway inhibits neointimal hyperplasia by suppressing inflammation and oxidative stress

“…Redox and redox-related inflammation play a critical role in vascular dysfunction [45] , [46] , [47] , [48] . Due to the anti-inflammatory feature, CAP or α7nAChR also plays critical roles in redox biology.…”

Role of Glutaredoxin-1 and Glutathionylation in Cardiovascular Diseases

“…In contrast, inhibition of Glrx is also vital for the revascularization of limbs following ischemia [22][23][24]. Research implicates Glrx controls fine tuning of redox signaling and may be a potential therapeutic target in a wide range of pathologies in which oxidative stress is involved.…”