Abstract 330: Endothelial JNK Is Critically Required for Native Collateral Artery Development
Arterial occlusive diseases are major causes of morbidity and mortality in industrialized countries and represent a huge economic burden. The extent of the native collateral circulation is considered to be the most important determinant of the magnitude of tissue damage and subsequent functional impairment that ensues following an arterial occlusive event. Therefore, understanding the mechanisms responsible for collateral artery development may provide avenues for the design of strategies to enhance the collateral circulation in patients at risk for arterial occlusive diseases. Here, we identify a critical requirement for cJun-NH2-Terminal Kinase (JNK) in collateral artery development. Indeed, using immunofluorescence, microfil perfusion and three dimensional high resolution micro computed tomography (μCT) imaging techniques, we demonstrate that mice with compound JNK-deficiency in the vascular endothelium display abnormal collateral arteries, which are unable to restore blood perfusion following occlusion of a major artery leading to severe tissue necrosis in animal models of femoral and coronary artery occlusion. Furthermore, employing constitutive and inducible conditional deletion strategies, we demonstrate that JNK acts during the initial development of collateral arteries to ensure proper patterning and connectivity, but is, for the most part, dispensable for angiogenic and arteriogenic responses in adult mice. The defects in collateral artery development may reflect an enhanced sensitivity of JNK-deficient endothelial cells to cell death in specific contexts. This study introduces JNK as a major regulator of vascular development and highlights the crucial importance of the collateral circulation as the main defining factor in reducing the severity of tissue damage and functional impairment following arterial occlusive events.
Author Disclosures: K. Ramo: None. K. Sugamura: None. J.F. Keaney: None. R.J. Davis: None.
- © 2014 by American Heart Association, Inc.