Suppression of ischemia in arterial occlusive disease by JNK-promoted native collateral artery development
- University of Massachusetts Medical School, United States
- UMASS Medical School, United States
Abstract
Arterial occlusive diseases are major causes of morbidity and mortality. Blood flow to the affected tissue must be restored quickly if viability and function are to be preserved. We report that disruption of the mixed-lineage protein kinase (MLK) - cJun NH2-terminal kinase (JNK) signaling pathway in endothelial cells causes severe blockade of blood flow and failure to recover in the murine femoral artery ligation model of hindlimb ischemia. We show that the MLK-JNK pathway is required for the formation of native collateral arteries that can restore circulation following arterial occlusion. Disruption of the MLK-JNK pathway causes decreased Dll4/Notch signaling, excessive sprouting angiogenesis, and defects in developmental vascular morphogenesis. Our analysis demonstrates that the MLK-JNK signaling pathway is a key regulatory mechanism that protects against ischemia in arterial occlusive disease.
Data availability
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Suppression of ischemia in arterial occlusive disease by JNK-promoted native collateral artery developmentPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE71159).
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Author details
Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK107220)
- Roger J Davis
National Heart, Lung, and Blood Institute (R01HL09122)
- John Keaney
Howard Hughes Medical Institute (Investigatorship)
- Roger J Davis
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#A1032) of the University of Massachusetts Medical School, Tufts University School of Medicine, and Brigham & Women's Hospital.
Copyright
© 2016, Ramo et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Suppression of ischemia in arterial occlusive disease by JNK-promoted native collateral artery development
eLife 5:e18414.
https://doi.org/10.7554/eLife.18414
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