Suppression of ischemia in arterial occlusive disease by JNK-promoted native collateral artery development
Kasmir Ramo,
Koichi Sugamura,
Siobhan Craige,
John F Keaney Jr,
Roger J Davis
Affiliations
Kasmir Ramo
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
Koichi Sugamura
Cardiovascular Medicine Division, University of Massachusetts Medical School, Worcester, United States; Department of Medicine, University of Massachusetts Medical School, Worcester, United States
Siobhan Craige
Cardiovascular Medicine Division, University of Massachusetts Medical School, Worcester, United States; Department of Medicine, University of Massachusetts Medical School, Worcester, United States
John F Keaney Jr
Cardiovascular Medicine Division, University of Massachusetts Medical School, Worcester, United States; Department of Medicine, University of Massachusetts Medical School, Worcester, United States
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States; Howard Hughes Medical Institute, Worcester, United States
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.
