Editors' ChoiceAngiogenesis

Tale of Reactive Oxygen Species Retold

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Science Translational Medicine  29 Aug 2012:
Vol. 4, Issue 149, pp. 149ec154
DOI: 10.1126/scitranslmed.3004805

New blood vessel formation—neoangiogenesis—is needed throughout life, from its essential role in early development to its ongoing contribution to wound healing. But the sprouting of new capillaries and blood vessels also is an essential step for cancer growth and metastasis and, in the retina, accounts for the leading cause of vision loss in older adults, macular degeneration. Now, Okuno and colleagues identify a new pathological neoangiogenesis pathway that involves the ataxia telangiectasia–mutated kinase (ATMK).

ATMK functions in cellular DNA damage responses, and hereditary defects in the ATMK gene cause the neurodegenerative disease ataxia telangiectasia. In addition to its role in DNA damage responses, ATMK has been linked with maintenance of redox balance: Formation of reactive oxygen species (ROS) activates ATMK, which results in up-regulation of antioxidant synthesis.

Okuno et al. demonstrated, in a mouse model of ischemia-reperfusion–induced retinopathy and in a melanoma mouse model, that ATKM was activated, in response to ROS, in immature blood vessel–associated endothelial cells, promoting pathological angiogenesis. Activation of ATMK also resulted in the up-regulation of antioxidants and subsequent ROS suppression as well as inhibition of the signaling protein mitogen-activated protein kinase p38α, which induces growth arrest and apoptosis in response to ROS. However, the observed effect of endothelial ATMK on neovascularization was independent of its effect on DNA damage and functioned without the vascular endothelial growth factor (VEGF) system, which is one of the driving forces of neoangiogenesis.

The new findings might lead to a way to circumvent problems with VEGF inhibitors, which currently are used to block pathological angiogenesis. VEGF inhibitors can damage the healthy vasculature, and some patients develop resistance to the drugs. The demonstration by Okuno et al.— that suppressing ROS formation by activation of ATMK promotes endothelial proliferation independent of VEFG signaling and without affecting normal vascular regeneration—opens potential new therapeutic avenues. The new drugs might influence the oxidative pathway downstream of ATMK in a favorable way without affecting its role in the DNA damage response.

Y. Okuno et al., Pathological neoangiogenesis depends on oxidative stress regulation by ATM. Nat. Med. 18, 1208–1216 (2012). [Abstract]

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