title: Suppression of ischemia in arterial occlusive disease by JNK-promoted native collateral artery development.
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.
authors: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States.
authors: Kasmir
authors: K
authors: Ramo
authors: Cardiovascular Medicine Division, University of Massachusetts Medical School, Worcester, United States.|Department of Medicine, University of Massachusetts Medical School, Worcester, United States.
authors: Koichi
authors: K
authors: Sugamura
authors: Cardiovascular Medicine Division, University of Massachusetts Medical School, Worcester, United States.|Department of Medicine, University of Massachusetts Medical School, Worcester, United States.
authors: Siobhan
authors: S
authors: Craige
authors: Cardiovascular Medicine Division, University of Massachusetts Medical School, Worcester, United States.|Department of Medicine, University of Massachusetts Medical School, Worcester, United States.
authors: John F
authors: JF
authors: Keaney
authors: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States.|Howard Hughes Medical Institute, Worcester, United States.
authors: Roger J
authors: 0000-0002-0130-1652
authors: RJ
authors: Davis
mesh_terms: D000818:Animals; D001157:Arterial Occlusive Diseases / Q000473:pathology*; D004195:Disease Models, Animal; D005263:Femoral Artery / Q000473:pathology* / Q000502:physiology; D007511:Ischemia / Q000473:pathology*; D020930:MAP Kinase Kinase Kinases / Q000032:analysis*; D020935:MAP Kinase Signaling System; D051379:Mice; D009024:Morphogenesis; D018919:Neovascularization, Physiologic
chemical_list: D020930:MAP Kinase Kinase Kinases
keywords: JNK; MLK; angiogenesis; cell biology; collateral arteries; collaterogenesis; developmental biology; mouse; stem cells