Journal
JOURNAL OF THE ROYAL SOCIETY INTERFACE
Volume 10, Issue 78, Pages -Publisher
ROYAL SOC
DOI: 10.1098/rsif.2012.0548
Keywords
endothelial cells; angiogenesis; electric field; MAPK; ERK
Categories
Funding
- NIH/NDDK [1R21DK078814-01A1]
- American Heart Association [BGIA- 533 0765425B]
- N.S.F. [DMR-1206784, DMR 0804199]
- Nanomedicine Fellowship (University of Cincinnati Nanomedicine Group)
- University of Cincinnati Biomedical Engineering department
- University of Cincinnati Physics department
- Division Of Materials Research
- Direct For Mathematical & Physical Scien [0804199] Funding Source: National Science Foundation
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Low-amplitude electric field (EF) is an important component of wound-healing response and can promote vascular tissue repair; however, the mechanisms of action on endothelium remain unclear. We hypothesized that physiological amplitude EF regulates angiogenic response of microvascular endothelial cells via activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway. A custom set-up allowed non-thermal application of EF of high (7.5 GHz) and low (60 Hz) frequency. Cell responses following up to 24 h of EF exposure, including proliferation and apoptosis, capillary morphogenesis, vascular endothelial growth factor (VEGF) expression and MAPK pathways activation were quantified. A db/db mouse model of diabetic wound healing was used for in vivo validation. High-frequency EF enhanced capillary morphogenesis, VEGF release, MEK-cRaf complex formation, MEK and ERK phosphorylation, whereas no MAPK/JNK and MAPK/p38 pathways activation was observed. The endothelial response to EF did not require VEGF binding to VEGFR2 receptor. EF-induced MEK phosphorylation was reversed in the presence of MEK and Ca2+ inhibitors, reduced by endothelial nitric oxide synthase inhibition, and did not depend on PI3K pathway activation. The results provide evidence for a novel intracellular mechanism for EF regulation of endothelial angiogenic response via frequency-sensitive MAPK/ERK pathway activation, with important implications for EF-based therapies for vascular tissue regeneration.
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