Journal
CIRCULATION RESEARCH
Volume 96, Issue 8, Pages 838-846Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000163633.10240.3b
Keywords
angiogenesis; AMP-activated protein kinase; vascular endothelial growth factor; p38 mitogen-activated protein kinase; skeletal muscle
Funding
- NHLBI NIH HHS [HL77774] Funding Source: Medline
- NIAMS NIH HHS [AR40197] Funding Source: Medline
- NIA NIH HHS [AG15052, AG17241] Funding Source: Medline
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AMP-activated protein kinase ( AMPK) is regulated by various cellular stresses. Vascular endothelial growth factor ( VEGF), a key regulator of angiogenesis, is also upregulated by several stress-inducible factors such as hypoxia and stimulation by cytokines and growth factors. Here, we investigated whether AMPK signaling in muscle has a role in regulating VEGF-mediated angiogenic processes. AICAR stimulated VEGF mRNA and protein levels in C2C12 myotube cultures. Transduction with dominant-negative AMPK abolished AICAR-induced VEGF expression at both steady state mRNA and protein levels. AICAR increased VEGF mRNA stability without affecting VEGF promoter activity. AICAR also stimulated p38 mitogen-activated protein kinase ( p38 MAPK) phosphorylation. Activation of p38 MAPK was suppressed by transduction with dominant-negative AMPK, suggesting that AMPK is upstream of p38 MAPK. The p38 MAPK inhibitor SB203580 blocked AICAR-induced increase in VEGF mRNA and protein levels, indicating that AICAR-mediated VEGF induction is dependent on p38 MAPK signaling. AICAR treatment increased VEGF expression and accelerated angiogenic repair of ischemic hindlimbs in mice in an AMPK-dependent manner. These data indicate that AMPK-p38 MAPK signaling cascade can increase VEGF production in muscle and promote angiogenesis in response to ischemic injury.
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