Impaired expression of uncoupling protein 2 causes defective postischemic angiogenesis in mice deficient in AMP-activated protein kinase α subunits

Ming-Jiang Xu, Ping Song, Najeeb Shirwany, Bin Liang, Junjie Xing, Benoit Viollet, Xian Wang, Yi Zhu, Ming-Hui Zou
Arteriosclerosis, Thrombosis, and Vascular Biology 2011, 31 (8): 1757-65

OBJECTIVE: The aim of the present study was to determine whether mitochondrial uncoupling protein (UCP) 2 is required for AMPK-dependent angiogenesis in ischemia in vivo.

METHODS AND RESULTS: Angiogenesis was assayed by monitoring endothelial tube formation (a surrogate for angiogenesis) in human umbilical vein endothelial cells (ECs), isolated mouse aortic endothelial cells (MAECs), and pulmonary microvascular endothelial cells or in ischemic thigh adductor muscles from wild-type (WT) mice or mice deficient in either AMPKα1 or AMPKα2. AMPK inhibition with pharmacological inhibitor (compound C) or genetic means (transfection of AMPKα-specific small interfering RNA) significantly lowered the tube formation in human umbilical vein ECs. Consistently, compared with WT mice, tube formation in MAECs isolated from either AMPKα1(-/-) or AMPKα2(-/-) mice, which exhibited oxidative stress and reduced expression of UCP2, was significantly impaired. In addition, adenoviral overexpression of UCP2, but not adenoviruses encoding green fluorescent protein, normalized tube formation in MAECs from either AMPKα1(-/-) or AMPKα2(-/-) mice. Similarly, supplementation with sodium nitroprusside, a nitric oxide (NO) donor, restored tube formation. Furthermore, ischemia significantly increased angiogenesis, serine 1177 phosphorylation of endothelial NO synthase, and UCP2 in ischemic thigh adductor muscles from WT mice but not in those from either AMPKα1(-/-) or AMPKα2(-/-) mice.

CONCLUSIONS: We conclude that AMPK-dependent UCP2 expression in ECs promotes angiogenesis in vivo.

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