Mary Jo Mulligan-Kehoe, Ph.D.
Associate Professor of Surgery
Ph.D. Biochemistry, International Institute of Molecular and Cellular Pathology, Catholic University of Louvain, Brussels, Belgium
Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD
1998-2006 Research Assistant Professor, Department of Surgery, Vascular Section , Dartmouth Medical School
2006-2009 Research Associate Professor, Department of Surgery, Vascular Section, Dartmouth Medical School
2009-present Associate Professor, Department of Surgery, Vascular Section, Dartmouth Medical School, Hanover, NH
Heart and Vascular Research Center
Norris Cotton Cancer Center
Program in Experimental and Molecular Medicine
Dartmouth Medical School
Borwell 530E, 1 Medical Center Drive
Lebanon, NH 03756
Lebanon NH 03756
Office: Borwell 530E
Asst. Phone: Laboratory 603-650-7614
The research in Dr. Mulligan-Kehoe's laboratory focuses on angiogenesis in mouse models of atherosclerosis using recombinant truncated PAI-1 proteins that have either anti-angiogenic or pro-angiogenic activity. The PAI-1 isoforms were discovered and developed in Dr. Mulligan-Kehoe's laboratory. Most of the attention to date has been on rPAI-123, which is a potent inhibitor of angiogenesis in tumors and in the vasa vasorum of hypercholesterolemic mice. Studies have shown that rPAI-123 inhibits angiogenic vessels by stimulating endothelial cell apoptosis to result in reduced vascularity. Additionally, it regulates plasmin activity through novel interactions with plasminogen to result in angiogenic vessel collapse. Collapse of the angiogenic vessels corresponds to plaque regression., suggesting that rPAI-123 has potential therapeutic applications. Additionally, rPAI-123 is used as a tool to dissect the the yet unknown biological processes that are required for expansion of the vasa vasorum in the disease process.
Dr. Mulligan-Kehoe's laboratory uses various imaging modalities to gain insight into the critical events that regulate the angiogenic process in atherosclerosis. The imaging techniques have enabled the lab to define the structure of the vasa vasorum and visualize the spatial distribution of key molecules that control the vasa vasorum network. Molecular imaging is an important component of her research and provides the laboratory with many cross disciplinary interactions.
Rotations and Thesis Projects:
Rotation project: Isolation of plasminogen domains to identify the binding sites for rPAI-123 and PAI-1 that modify plasmin activity.
Rotation project: Determine the binding affinity of rPAI-123 and PAI-1 for plasminogen.
Rotation project: Identify the adventitial cell types that produce FGF-2. Visualize, by confocal microscopy, the spatial distribution of FGF-2 and macrophages relative to angiogenic vasa vasorum in the adventitia of atherosclerotic mice.
Thesis project: Investigate the ability of a pro-angiogenic truncated PAI-1 protein to promote collateral growth in a mouse model of hindlimb ischemia.
Mechanisms of PAI-1 Induced Anti-Angiogenesis
NIH/ NHLBI, R01, Years 5-8
PI: MJ Mulligan-Kehoe
Dysregulated Angiogenesis in Scleroderma-Associated PAH
Co-I: MJ Mulligan-Kehoe
PEMM 275 (vascular biology)
Mulligan-Kehoe MJ, Wagner R, Wieland C, Powell R. A truncated plasminogen activator inhibitor-1 protein inhibits angiostatin (K1-3), a plasminogen cleavage product. J. Biol. Chem. 276(11):8588-8596, 2001. (view details on MedLine)
Mulligan-Kehoe MJ, Kleinman HK, Drinane M, Wieland C, Wagner RJ, Powell RJ A truncated plasminogen activator inhibitor-1 protein blocks the availability of heparin-binding VEGF-A isoforms. J. Biol. Chem. 277(50): 49077-49089, 2002 (view details on MedLine)
Drinane MC, Sherman JA, Hall AE, Simons M, Mulligan-Kehoe MJ. Plasminogen and plasmin activity in patients with coronary artery disease. J. Thromb. Haem. 4: 1288-1295, 2006. (view details on MedLine)
Drinane M, Walsh J, Mollmark J, Simons M, Mulligan-Kehoe MJ The anti-angiogenic activity of rPAI-1 23 inhibits fibroblast growth factor-2 functions. J. Biol. Chem. 281:33336-33344, 2006 (view details on MedLine)
Mulligan-Kehoe MJ, Drinane MC, Mollmark J, Casciola-Rosen L, Hummers LK, Hall A, Rosen A, Wiigley FM, Simons M Antiangiogenic plasma activity in patients with systemic sclerosis. Arthritis Rheum. 56: 3448-58, 2007 (view details on MedLine)
Drinane M, Mollmark J, Zagorchev L, Moodie K, Sun B, Hall A, Shipman S, Morganelli P, Simons M, Mulligan-Kehoe MJ The Antiangiogenic Activity of rPAI-123 Inhibits Vasa Vasorum and Growth of Atherosclerotic Plaque. Circ Res. 104:337-45, 2009. (view details on MedLine)
Mulligan-Kehoe MJ. The Vasa Vasorum in Diseased and Non-Diseased Arteries. Amer JPhysiol-Heart and Circulatory Physiology 298: H295-305, 2010 (view details on MedLine)
Ren B, Mukhopadhyaym A, Lanahan A, Zhuang ZW, Moodie KL, Mulligan-Kehoe MJ, Byzova TV, Peterson RT, Simons M Erk1/2-Akt1 cross-talk-dependent regulation of arteriogenesis. J. Clin. Invest., 120:1217-28, 2010 (view details on MedLine)
Kuzontkoski de Fernández PM, Mulligan-Kehoe MJ, Harris BT, Israel MA. Inhibitor of differentiation-4 promotes angiogenesis and the growth of glioblastoma by elevating matrix GLA levels. Oncogene, 29:3793-802, 2010 (view details on MedLine)
Zagorchev L and Mulligan-Kehoe MJ Molecular Imaging of Vessels in Mouse Models of Disease. Eur. J Radiology. 70: 305–311, 2009 (view details on MedLine)