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.
Highlights
Ischemic stroke, myocardial infarction and peripheral artery disease result from arterial occlusion that blocks blood flow leading to severe tissue ischemia and necrosis
CJun, cJun, Jun NH2-terminal kinase (JNK), Cdh5, and GAPDH. (C) Representative laser doppler images showing blood perfusion in the hindlimbs of WT and Map3k10-/- Map3k11-/- mice mice prior to unilateral femoral artery (FA) ligation (Pre-femoral artery ligation (FAL)) and post-FAL. (D) Quantitation of hindlimb blood flow demonstrated that MLK2/3-deficient mice exhibited significantly increased blood perfusion blockade and no recovery by day 3 post-FAL compared with control mice. (E) Representative images of mouse paws on Day 4 post-FAL
Primary murine lung endothelial cells (MLEC) isolated from E3KO mice (Figure 1—figure supplement 1D,E) demonstrated reduced JNK expression compared with MLEC from control mice (Figure 1A)
Summary
Myocardial infarction and peripheral artery disease result from arterial occlusion that blocks blood flow leading to severe tissue ischemia and necrosis. Collaterals are artery-toartery or arteriole-to-arteriole interconnections that can bypass an occlusion by providing an alternative route for blood flow to the affected tissue that restores tissue homeostasis and limits tissue damage (Antoniucci et al, 2002; Schaper, 2009; Faber et al, 2014; Simons and Eichmann, 2015). More blood flow is diverted to the collateral circulation and this increased flow and sheer stress in collateral arteries initiates a number of processes that result in the outward remodeling (arteriogenesis) of these vessels into efficient conductance arteries (Heil et al, 2006; Schaper, 2009; van Royen et al, 2009; Simons and Eichmann, 2015).
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