Mechanisms of PAI-1 Induced Anti-Angiogenesis

Summary

Principal Investigator: Mary Jo Mulligan-Kehoe
Abstract: Neovascularization is associated with atherosclerosis and the vasa vasorum is the primary source of angiogenic vessels that supply the neovascularized area. There is evidence that vasa vasorum density increases during plaque progression, but it remains uncertain that angiogenesis has a major role in atherosclerotic plaque growth. We have shown that a truncated plasminogen activator inhibitor-1 (PAI-1) protein, rPAI-123, has significant anti-angiogenic activity. Studies performed in this funding period show that rPAI-123 inhibits fibroblast growth factor-2 (FGF2) signaling pathways and functions. We hypothesized that rPAI-123 would inhibit angiogenic vasa vasorum in atherogenic mice to result in reduced plaque progression. The hypothesis was tested in female LDLR-/-/ ApoB-100 mice that received a high fat diet for 14 weeks prior to initiating 6 weeks of rPAI-123 (n=16) or saline (n=11) treatment with continued high fat diet. Seven control animals received normal chow diet and saline treatment. The ratio of lipid area: total area in Sudan 4 stained vessels was 60% (p<0.001) less in the descending aorta and 30% (p<0.001) less in the aortic root of rPAI-123 treated animals when compared to high fat, saline treated mice. Reconstructed confocal microscopy images of CD31- probed vessels in the plaque area show that rPAI-123 reduced vessel area and length by 43 and 37% (p = 0.01), respectively when compared to high fat, saline treated controls. The left carotid artery circumference in high fat, rPAI-123 and high fat, saline groups were 24% (p=0.05) greater than the chow fed control. However, treatment with rPAI-123 reduced plaque area by 67% (p<0.001) and increased lumen area by 74% (p<0.001) when compared to the high fat, saline group. These data strongly support our hypothesis and additionally suggest that rPAI-123 promotes plaque regression. This proposal will further examine plaque regression in response to rPAI-123 in atherogenic female LDLR-/-/ ApoB-100 mice. Opposing effects of rPAI-123 on native PAI-1 functions will be studied in PAI-1-/-/ LDLR-/-/ ApoB-100. Finally, rPAI-123 binding interactions with potential candidate receptors will be investigated. Current medical treatment for atherosclerotic disease potentially prevents progression. A molecule that promotes plaque regression would provide profound medical advancement, thus making the proposed studies highly significant. Atherosclerosis is a prevalent vascular disease among Americans and is a leading cause of death. We have produced a truncated PAI-1 protein, rPAI-123, that has significant anti-angiogenic activity. Our preliminary results with rPAI-123 are novel, demonstrating for the first time that a modified PAI-1 protein can inhibit angiogenic vessels in a mouse model of atherosclerosis and promote plaque regression. These observations raise the possibility that rPAI-123 may ultimately have a therapeutic role in atherosclerosis. Current medical treatment for atherosclerotic disease potentially prevents progression, therefore, a molecule that promotes plaque regression would provide profound medical advancement, thus making the proposed studies highly significant.
Funding Period: ----------------2002 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Plasminogen and plasmin activity in patients with coronary artery disease
    M C Drinane
    Department of Surgery, Vascular Section, Dartmouth Medical School, Lebanon, NH 03756, USA
    J Thromb Haemost 4:1288-95. 2006
  2. ncbi The anti-angiogenic activity of rPAI-1(23) inhibits fibroblast growth factor-2 functions
    Mary Drinane
    Department of Surgery, Vascular Section, Dartmouth Medical School, Lebanon, NH 03756, USA
    J Biol Chem 281:33336-44. 2006
  3. ncbi Antiangiogenic plasma activity in patients with systemic sclerosis
    Mary Jo Mulligan-Kehoe
    Angiogenesis Research Center, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA
    Arthritis Rheum 56:3448-58. 2007
  4. doi Vascular disease in scleroderma: angiogenesis and vascular repair
    Mary Jo Mulligan-Kehoe
    Angiogenesis Research Center, Dartmouth Hitchcock Medical Center, Dartmouth Medical School, Borwell 530 E, 1 Medical Center Drive, Lebanon, NH 03756, USA
    Rheum Dis Clin North Am 34:73-9; vi. 2008
  5. pmc Fibroblast growth factor-2 is required for vasa vasorum plexus stability in hypercholesterolemic mice
    Jessica I Mollmark
    Department of Surgery, Vascular Section, Dartmouth Medical School, Borwell 530 E 1 Medical Center Dr, Lebanon, NH 03756, USA
    Arterioscler Thromb Vasc Biol 32:2644-51. 2012
  6. pmc Anti-angiogenic activity of rPAI-1(23) and vasa vasorum regression
    Mary Jo Mulligan-Kehoe
    Department of Surgery, Vascular Section, The Geisel School of Medicine at Dartmouth, Borwell 530E, 1 Medical Center Drive, Lebanon, NH 03756, USA
    Trends Cardiovasc Med 23:114-20. 2013
  7. pmc The antiangiogenic activity of rPAI-1(23) inhibits vasa vasorum and growth of atherosclerotic plaque
    Mary Drinane
    Angiogenesis Research, Dartmouth Medical School, Lebanon, NH 03756, USA
    Circ Res 104:337-45. 2009
  8. pmc Molecular imaging of vessels in mouse models of disease
    Lyubomir Zagorchev
    Angiogenesis Research Center, Dartmouth Medical School, Lebanon, NH 03756, USA
    Eur J Radiol 70:305-11. 2009
  9. pmc The vasa vasorum in diseased and nondiseased arteries
    Mary Jo Mulligan-Kehoe
    Department of Surgery, Vascular Section, Dartmouth Medical School, Borwell 530E, One Medical Center Drive, Lebanon, NH 03756, USA
    Am J Physiol Heart Circ Physiol 298:H295-305. 2010
  10. pmc ERK1/2-Akt1 crosstalk regulates arteriogenesis in mice and zebrafish
    Bin Ren
    Department of Cell Biology, Cleveland Clinic Foundation, Ohio, USA
    J Clin Invest 120:1217-28. 2010

Scientific Experts

  • Mary Jo Mulligan-Kehoe
  • Michael Simons
  • Jessica Mollmark
  • Mary Drinane
  • Lyubomir Zagorchev
  • Clinton S Robbins
  • Jessica I Mollmark
  • L Zagorchev
  • Baiming Sun
  • Samantha Shipman
  • Bin Ren
  • M C Drinane
  • Takuya Ueno
  • Rostic Gorbatov
  • Justin Kim
  • Matthias Nahrendorf
  • Georg F Weber
  • Andrew J H Park
  • Martin Etzrodt
  • Sarah Katzenell
  • Yoshiko Iwamoto
  • Nico Van Rooijen
  • Filip K Swirski
  • Ralph Weissleder
  • Jose Luiz Figueiredo
  • Peter Libby
  • Lyubomir G Zagorchev
  • Thomas Z Wang
  • Mikael J Pittet
  • Samantha L Shipman
  • Aleksey Chudnovskiy
  • Philipp J Rauch
  • Saranya Ravi
  • Maarten Buitendijk
  • Zhen W Zhuang
  • Tatiana V Byzova
  • Arpita Mukhopadhyay
  • Randall T Peterson
  • Anthony A Lanahan
  • Yong Deng
  • Karen L Moodie
  • Amy Hall
  • Karen Moodie
  • Peter Morganelli
  • A E Hall
  • Jannine Walsh
  • M Simons
  • J A Sherman

Detail Information

Publications13

  1. ncbi Plasminogen and plasmin activity in patients with coronary artery disease
    M C Drinane
    Department of Surgery, Vascular Section, Dartmouth Medical School, Lebanon, NH 03756, USA
    J Thromb Haemost 4:1288-95. 2006
    ..We hypothesized that interactions of tissue plasminogen activator (tPA) with Plg kringle domains regulates plasmin levels in patients with stable CAD...
  2. ncbi The anti-angiogenic activity of rPAI-1(23) inhibits fibroblast growth factor-2 functions
    Mary Drinane
    Department of Surgery, Vascular Section, Dartmouth Medical School, Lebanon, NH 03756, USA
    J Biol Chem 281:33336-44. 2006
    ..The rPAI-1(23) anti-angiogenic activity inhibits FGF2 pro-angiogenic functions by blocking FGF2 signaling through FGF receptor 1 and syndecan-4 and downstream effectors p-Akt, p-JNK, and p-c-Jun...
  3. ncbi Antiangiogenic plasma activity in patients with systemic sclerosis
    Mary Jo Mulligan-Kehoe
    Angiogenesis Research Center, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA
    Arthritis Rheum 56:3448-58. 2007
    ..The aim of this study was to investigate the presence of antiangiogenic factors in patients with SSc...
  4. doi Vascular disease in scleroderma: angiogenesis and vascular repair
    Mary Jo Mulligan-Kehoe
    Angiogenesis Research Center, Dartmouth Hitchcock Medical Center, Dartmouth Medical School, Borwell 530 E, 1 Medical Center Drive, Lebanon, NH 03756, USA
    Rheum Dis Clin North Am 34:73-9; vi. 2008
    ..Although most aspects of vascular injury in scleroderma are poorly understood, certain biologic themes are beginning to emerge that are important in understanding scleroderma-related vascular disease...
  5. pmc Fibroblast growth factor-2 is required for vasa vasorum plexus stability in hypercholesterolemic mice
    Jessica I Mollmark
    Department of Surgery, Vascular Section, Dartmouth Medical School, Borwell 530 E 1 Medical Center Dr, Lebanon, NH 03756, USA
    Arterioscler Thromb Vasc Biol 32:2644-51. 2012
    ..FGF-2 seems to play a role in the formation of a distinct vasa vasorum network. This study examined the vasa vasorum structure and its relationship to FGF-2...
  6. pmc Anti-angiogenic activity of rPAI-1(23) and vasa vasorum regression
    Mary Jo Mulligan-Kehoe
    Department of Surgery, Vascular Section, The Geisel School of Medicine at Dartmouth, Borwell 530E, 1 Medical Center Drive, Lebanon, NH 03756, USA
    Trends Cardiovasc Med 23:114-20. 2013
    ..This mechanism contributes significantly to vasa vasorum regression/collapse and is discussed as a model of regression...
  7. pmc The antiangiogenic activity of rPAI-1(23) inhibits vasa vasorum and growth of atherosclerotic plaque
    Mary Drinane
    Angiogenesis Research, Dartmouth Medical School, Lebanon, NH 03756, USA
    Circ Res 104:337-45. 2009
    ....
  8. pmc Molecular imaging of vessels in mouse models of disease
    Lyubomir Zagorchev
    Angiogenesis Research Center, Dartmouth Medical School, Lebanon, NH 03756, USA
    Eur J Radiol 70:305-11. 2009
    ..The basic principles of the imaging modalities are described and experimental results are presented...
  9. pmc The vasa vasorum in diseased and nondiseased arteries
    Mary Jo Mulligan-Kehoe
    Department of Surgery, Vascular Section, Dartmouth Medical School, Borwell 530E, One Medical Center Drive, Lebanon, NH 03756, USA
    Am J Physiol Heart Circ Physiol 298:H295-305. 2010
    ..Atherosclerosis is a multifactorial disease. There is increasing evidence that factors, produced in response to changes in the arterial wall, collaborate with the vasa vasorum to enhance the disease process...
  10. pmc ERK1/2-Akt1 crosstalk regulates arteriogenesis in mice and zebrafish
    Bin Ren
    Department of Cell Biology, Cleveland Clinic Foundation, Ohio, USA
    J Clin Invest 120:1217-28. 2010
    ..We therefore conclude that PI3K-ERK1/2 crosstalk plays a key role in the regulation of arterial growth and that the augmentation of ERK signaling via suppression of the PI3K signaling pathway can effectively stimulate arteriogenesis...
  11. pmc Advances in imaging angiogenesis and inflammation in atherosclerosis
    L Zagorchev
    Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire, USA
    Thromb Haemost 105:820-7. 2011
    ....
  12. pmc Antiangiogenic activity of rPAI-1(23) promotes vasa vasorum regression in hypercholesterolemic mice through a plasmin-dependent mechanism
    Jessica Mollmark
    Department of Surgery, Vascular Section, Dartmouth Medical School, Borwell 530 E, 1 Medical Center Dr, Lebanon, NH 03756, USA
    Circ Res 108:1419-28. 2011
    ....
  13. pmc Extramedullary hematopoiesis generates Ly-6C(high) monocytes that infiltrate atherosclerotic lesions
    Clinton S Robbins
    Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Simches Research Bldg, 185 Cambridge St, Boston, MA 02114, USA
    Circulation 125:364-74. 2012
    ..Here, we hypothesized that the bone marrow outsources the production of Ly-6C(high) monocytes during atherosclerosis...