Program in Molecular Medicine
First Thesis Advisor
Roger J. Davis, PhD
Arterial Occlusive Diseases, Collateral Circulation, Endothelial Cells, Vascular Endothelium, Hematopoietic Stem Cells, Hematopoiesis, MAP Kinase Signaling System, JNK Mitogen-Activated Protein Kinases
Dissertations, UMMS; Arterial Occlusive Diseases; Collateral Circulation; Endothelial Cells; Endothelium, Vascular; Hematopoietic Stem Cells; Hematopoiesis; MAP Kinase Signaling System; JNK Mitogen-Activated Protein Kinases
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 an important determinant of blood perfusion restoration and therefore the severity of tissue damage and functional impairment that ensues following arterial occlusion. Understanding the mechanisms responsible for collateral artery development may provide avenues for therapeutic intervention. Here, we identify a critical requirement for mixed lineage kinase (MLK) – cJun-NH2-terminal kinase (JNK) signaling in vascular morphogenesis and native collateral artery development. We demonstrate that Mlk2-/-Mlk3-/- mice or mice with compound JNK-deficiency in the vascular endothelium display abnormal collateral arteries, which are unable to restore blood perfusion following arterial occlusion, leading to severe tissue necrosis in animal models of femoral and coronary artery occlusion. Employing constitutive and inducible conditional deletion strategies, we demonstrate that endothelial JNK acts during the embryonic development of collateral arteries to ensure proper patterning and maturation, but is dispensable for angiogenic and arteriogenic responses in adult mice. During developmental vascular morphogenesis, MLK – JNK signaling is required for suppression of excessive sprouting angiogenesis likely via JNK-dependent regulation of Dll4 expression and Notch signaling. This function of JNK may underlie its critical requirement for native collateral artery formation. Thus, this study introduces MLK – JNK signaling as a major regulator of vascular development.
In contrast, we find that JNK in hematopoietic cells, which are thought to share a common mesodermally-derived precursor with endothelial cells, is cellautonomously dispensable for normal hematopoietic development and hematopoietic stem cell self-renewal, illustrating the highly context dependent function of JNK.
Ramo, K. Jun Kinases in Hematopoiesis, and Vascular Development and Function: A Dissertation. (2015). University of Massachusetts Medical School. GSBS Dissertations and Theses. Paper 789. DOI: 10.13028/M2RW2P. http://escholarship.umassmed.edu/gsbs_diss/789
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Available for download on Friday, July 13, 2018