Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Antiangiogenic therapy for normalization of atherosclerotic plaque vasculature: a potential strategy for plaque stabilization

Nature Clinical Practice Cardiovascular Medicine volume 4, pages 491–502 (2007)Cite this article

Abstract

Angiogenesis within human atherosclerotic plaques has an important role in plaque progression as immature blood vessels leak red blood cells and inflammatory mediators into the plaque center. Accumulation of free cholesterol from red blood cell membranes potentially increases the size of the necrotic core and triggers a chain of events that promote plaque destabilization. Antiangiogenic agents have been shown to prune some tumor vessels and 'normalize' the structure and function of the remaining vasculature, thereby improving the access of chemotherapeutic agents to tumors. We propose that antiangiogenic therapy can similarly stabilize vulnerable 'rupture-prone' plaques by pruning and normalizing immature intraplaque vessels, preventing further intraplaque hemorrhage. This normalization would limit necrotic core enlargement, further luminal narrowing and the degree of inflammation. Such normalization has been realized using vascular endothelial growth factor antagonists for the treatment of cancer and age-related macular degeneration. The development of this novel approach to prevent plaque progression might add to the armamentarium of preventive measures for acute myocardial infarction, stroke and sudden cardiac death.

Key Points

  • Although the causes of atherosclerotic lesion progression from an asymptomatic fibroatheromatous plaque to a lesion at high risk of rupture (thin-cap fibroatheroma or 'vulnerable plaque') are not fully understood, data support the concept that intraplaque hemorrhage is critical for the progression of plaques into high-risk unstable lesions

  • On the basis of similarities with the structure of tumor vessels, we propose that judicious application of antiangiogenic agents could prune and normalize immature intraplaque blood vessels, thereby preventing intraplaque hemorrhage

  • A similar paradigm has been described in the wet form of age-related macular degeneration; pegaptanib, a aptamer that inhibits vascular endothelial growth factor, and ranibizumab, an antibody fragment that inhibits vascular endothelial growth factor, maintain or improve vision in these patients, suggesting that these agents normalize the vasculature in the eye

  • At present, there are serious obstacles to the testing of this concept, such as the lack of an appropriate animal model, uncertainty regarding the optimum agents and targets and appropriate dosing and delivery method, and difficulties in selecting patients suitable for this therapy

  • Further research in this nascent field of vascular normalization could result in the prevention of plaque progression and its clinical consequences

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The normalization hypothesis
Figure 2: Vasa vasorum in thin-cap fibroatheroma and plaque rupture compared with that in stable plaque in human
Figure 3: Proposed 'normalization' of plaque microvasculature and its implications in atherosclerotic angiogenesis

Similar content being viewed by others

References

  1. Burke AP et al. (1997) Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med 336: 1276–1282

    Article  CAS  Google Scholar 

  2. Milei J et al. (1998) Carotid rupture and intraplaque hemorrhage: immunophenotype and role of cells involved. Am Heart J 136: 1096–1105

    Article  CAS  Google Scholar 

  3. Kolodgie FD et al. (2003) Intraplaque hemorrhage and progression of coronary atheroma. N Engl J Med 349: 2316–2325

    Article  CAS  Google Scholar 

  4. Takaya N et al. (2005) Presence of intraplaque hemorrhage stimulates progression of carotid atherosclerotic plaques: a high-resolution magnetic resonance imaging study. Circulation 111: 2768–2775

    Article  Google Scholar 

  5. Virmani R et al. (2005) Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol 25: 2054–2061

    Article  CAS  Google Scholar 

  6. Jeziorska M and Woolley DE (1999) Local neovascularization and cellular composition within vulnerable regions of atherosclerotic plaques of human carotid arteries. J Pathol 188: 189–196

    Article  CAS  Google Scholar 

  7. Kockx MM et al. (2003) Phagocytosis and macrophage activation associated with hemorrhagic microvessels in human atherosclerosis. Arterioscler Thromb Vasc Biol 23: 440–446

    Article  CAS  Google Scholar 

  8. Virmani R et al. (1998) When neoangiogenesis ricochets. Am Heart J 136: 937–939

    Article  CAS  Google Scholar 

  9. Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307: 58–62

    Article  CAS  Google Scholar 

  10. Jain RK et al. (2006) Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat Clin Pract Oncol 3: 24–40

    Article  CAS  Google Scholar 

  11. Batchelor TT et al. (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11: 83–95

    Article  CAS  Google Scholar 

  12. Jain RK (2001) Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7: 987–989

    Article  CAS  Google Scholar 

  13. Virmani R et al. (2000) Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 20: 1262–1275

    Article  CAS  Google Scholar 

  14. Gerrity RG (1981) The role of the monocyte in atherogenesis: II. Migration of foam cells from atherosclerotic lesions. Am J Pathol 103: 191–200

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Tabas I et al. (1996) Evidence that the initial up-regulation of phosphatidylcholine biosynthesis in free cholesterol-loaded macrophages is an adaptive response that prevents cholesterol-induced cellular necrosis. Proposed role of an eventual failure of this response in foam cell necrosis in advanced atherosclerosis. J Biol Chem 271: 22773–22781

    Article  CAS  Google Scholar 

  16. Tabas I (2000) Cholesterol and phospholipid metabolism in macrophages. Biochim Biophys Acta 1529: 164–174

    Article  CAS  Google Scholar 

  17. Davis GE (1992) The Mac-1 and p150,95 beta 2 integrins bind denatured proteins to mediate leukocyte cell-substrate adhesion. Exp Cell Res 200: 242–252

    Article  CAS  Google Scholar 

  18. Hynes RO (1992) Integrins: versatility, modulation, and signaling in cell adhesion. Cell 69: 11–25

    Article  CAS  Google Scholar 

  19. Darbonne WC et al. (1991) Red blood cells are a sink for interleukin 8, a leukocyte chemotaxin. J Clin Invest 88: 1362–1369

    Article  CAS  Google Scholar 

  20. Vlodavsky I and Friedmann Y (2001) Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis. J Clin Invest 108: 341–347

    Article  CAS  Google Scholar 

  21. Kim-Shapiro DB et al. (2006) Unraveling the reactions of nitric oxide, nitrite, and hemoglobin in physiology and therapeutics. Arterioscler Thromb Vasc Biol 26: 697–705

    Article  CAS  Google Scholar 

  22. Graversen JH et al. (2002) CD163: a signal receptor scavenging haptoglobin-hemoglobin complexes from plasma. Int J Biochem Cell Biol 34: 309–314

    Article  CAS  Google Scholar 

  23. Moreno PR et al. (2006) Neovascularization in human atherosclerosis. Circulation 113: 2245–2252

    Article  Google Scholar 

  24. Van den Heuvel MM et al. (1999) Regulation of CD 163 on human macrophages: cross-linking of CD163 induces signaling and activation. J Leukoc Biol 66: 858–866

    Article  CAS  Google Scholar 

  25. Philippidis P et al. (2004) Hemoglobin scavenger receptor CD163 mediates interleukin-10 release and heme oxygenase-1 synthesis: antiinflammatory monocyte-macrophage responses in vitro, in resolving skin blisters in vivo, and after cardiopulmonary bypass surgery. Circ Res 94: 119–126

    Article  CAS  Google Scholar 

  26. Levy AP et al. (2007) Haptoglobin genotype is a determinant of iron, lipid peroxidation, and macrophage accumulation in the atherosclerotic plaque. Arterioscler Thromb Vasc Biol 27: 134–140

    Article  CAS  Google Scholar 

  27. O'Brien KD et al. (1996) Neovascular expression of E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in human atherosclerosis and their relation to intimal leukocyte content. Circulation 93: 672–682

    Article  CAS  Google Scholar 

  28. Melder RJ et al. (1996) During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium. Nat Med 2: 992–997

    Article  CAS  Google Scholar 

  29. Burke AP et al. (1999) Plaque rupture and sudden death related to exertion in men with coronary artery disease. JAMA 281: 921–926

    Article  CAS  Google Scholar 

  30. Fleiner M et al. (2004) Arterial neovascularization and inflammation in vulnerable patients: early and late signs of symptomatic atherosclerosis. Circulation 110: 2843–2850

    Article  Google Scholar 

  31. Moreno PR et al. (2004) Plaque neovascularization is increased in ruptured atherosclerotic lesions of human aorta: implications for plaque vulnerability. Circulation 110: 2032–2038

    Article  Google Scholar 

  32. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285: 1182–1186

    Article  CAS  Google Scholar 

  33. Carmeliet P and Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407: 249–257

    Article  CAS  Google Scholar 

  34. Zhang Y et al. (1993) Immunohistochemical study of intimal microvessels in coronary atherosclerosis. Am J Pathol 143: 164–172

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Dunmore BJ et al. (2007) Carotid plaque instability and ischemic symptoms are linked to immaturity of microvessels within plaques. J Vasc Surg 45: 155–159

    Article  Google Scholar 

  36. Jain RK (2003) Molecular regulation of vessel maturation. Nat Med 9: 685–693

    Article  CAS  Google Scholar 

  37. Van den Brenk HA et al. (1977) The significance of free blood in liquid and solid tumours. Br J Exp Pathol 58: 147–159

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Kohn S et al. (1992) Pathways of macromolecular tracer transport across venules and small veins. Structural basis for the hyperpermeability of tumor blood vessels. Lab Invest 67: 596–607

    CAS  PubMed  Google Scholar 

  39. Heistad DD and Armstrong ML (1986) Blood flow through vasa vasorum of coronary arteries in atherosclerotic monkeys. Arteriosclerosis 6: 326–331

    Article  CAS  Google Scholar 

  40. Moulton KS et al. (1999) Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E-deficient mice. Circulation 99: 1726–1732

    Article  CAS  Google Scholar 

  41. Chen YX et al. (1999) Immunohistochemical expression of vascular endothelial growth factor/vascular permeability factor in atherosclerotic intimas of human coronary arteries. Arterioscler Thromb Vasc Biol 19: 131–139

    Article  CAS  Google Scholar 

  42. Hansson GK (2001) Immune mechanisms in atherosclerosis. Arterioscler Thromb Vasc Biol 21: 1876–1890

    Article  CAS  Google Scholar 

  43. Laine P et al. (2000) Adventitial mast cells connect with sensory nerve fibers in atherosclerotic coronary arteries. Circulation 101: 1665–1669

    Article  CAS  Google Scholar 

  44. Shah PK et al. (1995) Human monocyte-derived macrophages induce collagen breakdown in fibrous caps of atherosclerotic plaques. Potential role of matrix-degrading metalloproteinases and implications for plaque rupture. Circulation 92: 1565–1569

    CAS  PubMed  Google Scholar 

  45. Lappalainen H et al. (2004) Mast cells in neovascularized human coronary plaques store and secrete basic fibroblast growth factor, a potent angiogenic mediator. Arterioscler Thromb Vasc Biol 24: 1880–1885

    Article  CAS  Google Scholar 

  46. Toth-Jakatics R et al. (2000) Cutaneous malignant melanoma: correlation between neovascularization and peritumor accumulation of mast cells overexpressing vascular endothelial growth factor. Hum Pathol 31: 955–960

    Article  CAS  Google Scholar 

  47. Des Guetz G et al. (2006) Microvessel density and VEGF expression are prognostic factors in colorectal cancer. Meta-analysis of the literature. Br J Cancer 94: 1823–1832

    Article  CAS  Google Scholar 

  48. Winkler F et al. (2004) Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6: 553–563

    CAS  PubMed  Google Scholar 

  49. Manegold C et al.; the BO17704 study group (2007) Randomised, double-blind multicentre phase III study of bevacizumab in combination with cisplatin and gemcitabine in chemotherapy-naïve patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC): BO17704. J Clin Oncol 25 (Suppl): 18S

    Google Scholar 

  50. Willett CG et al. (2004) Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10: 145–147

    Article  CAS  Google Scholar 

  51. Willett CG et al. (2005) Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a phase I trial in rectal cancer patients. J Clin Oncol 23: 8136–8139

    Article  Google Scholar 

  52. Aiello LP et al. (1995) Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci USA 92: 10457–10461

    Article  CAS  Google Scholar 

  53. Gragoudas ES et al. (2004) Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 351: 2805–2816

    Article  CAS  Google Scholar 

  54. Ferrara N et al. (2006) Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina 26: 859–870

    Article  Google Scholar 

  55. Fung AE et al. (2006) The International Intravitreal Bevacizumab Safety Survey: using the internet to assess drug safety worldwide. Br J Ophthalmol 90: 1344–1349

    Article  CAS  Google Scholar 

  56. Weiss MRD and Prenner JL (2007) The incidence of systemic adverse events in patients treated with intravitreal bevacizumab. Presented at the Association for Research in Vision and Ophthalmology, May 10 2007, Fort Lauderdale, FL

  57. Skillings JR et al. (2005) Arterial thromboembolic events (ATEs) in a pooled analysis of 5 randomized, controlled trials (RCTs) of bevacizumab (BV) with chemotherapy [abstract]. J Clin Oncol 23 (Suppl): S3019

    Article  Google Scholar 

  58. LiewM G and Mitchell P (2007) Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 356: 747–748

    Article  Google Scholar 

  59. Yang JC et al. (2003) A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349: 427–434

    Article  CAS  Google Scholar 

  60. Ratner M (2004) Genentech discloses safety concerns over Avastin. Nat Biotechnol 22: 1198

    Article  CAS  Google Scholar 

  61. Drimal J et al. (2006) Cardiovascular toxicity of the first line cancer chemotherapeutic agents: doxorubicin, cyclophosphamide, streptozotocin and bevacizumab. Neuroendocrinol Lett 27 (Suppl 2): S176–S179

    Google Scholar 

  62. Inai T et al. (2004) Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol 165: 35–52

    Article  CAS  Google Scholar 

  63. Munoz-Najar UM et al. (2006) Hypoxia stimulates breast carcinoma cell invasion through MT1-MMP and MMP-2 activation. Oncogene 25: 2379–2392

    Article  CAS  Google Scholar 

  64. Kamba T et al. (2006) VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature. Am J Physiol Heart Circ Physiol 290: H560–H576

    Article  CAS  Google Scholar 

  65. Autiero M et al. (2003) Placental growth factor and its receptor, vascular endothelial growth factor receptor-1: novel targets for stimulation of ischemic tissue revascularization and inhibition of angiogenic and inflammatory disorders. J Thromb Haemost 1: 1356–1370

    Article  CAS  Google Scholar 

  66. Khurana R et al. (2005) Role of angiogenesis in cardiovascular disease: a critical appraisal. Circulation 112: 1813–1824

    Article  Google Scholar 

  67. Johnson J et al. (2005) Plaque rupture after short periods of fat feeding in the apolipoprotein E-knockout mouse: model characterization and effects of pravastatin treatment. Circulation 111: 1422–1430

    Article  CAS  Google Scholar 

  68. Schwartz SM et al. (2007) Plaque rupture in humans and mice. Arterioscler Thromb Vasc Biol 27: 705–713

    Article  CAS  Google Scholar 

  69. Rosenfeld ME et al. (2000) Advanced atherosclerotic lesions in the innominate artery of the ApoE knockout mouse. Arterioscler Thromb Vasc Biol 20: 2587–2592

    Article  CAS  Google Scholar 

  70. Robertson AK (2003) Disruption of TGF-beta signaling in T cells accelerates atherosclerosis. J Clin Invest 112: 1342–1350

    Article  CAS  Google Scholar 

  71. Sasaki T et al. (2006) A simple method of plaque rupture induction in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 26: 1304–1309

    Article  CAS  Google Scholar 

  72. Gordon MS and Cunningham D (2005) Managing patients treated with bevacizumab combination therapy. Oncology 69 (Suppl 3): S25–S33

    Article  Google Scholar 

  73. Burke AP et al. (2001) Healed plaque ruptures and sudden coronary death: evidence that subclinical rupture has a role in plaque progression. Circulation 103: 934–940

    Article  CAS  Google Scholar 

  74. Luttun A et al. (2002) Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med 8: 831–840

    Article  CAS  Google Scholar 

  75. Verheul HM and Pinedo HM (2007) Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer 7: 475–485

    Article  CAS  Google Scholar 

  76. Weis M et al. (2002) Statins have biphasic effects on angiogenesis. Circulation 105: 739–745

    Article  CAS  Google Scholar 

  77. Tong RT et al. (2004) Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res 64: 3731–3736

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank Y Boucher, P Carmeliet, D Duda, D Fukumura, K Kozak, L Munn and T Padera for their input. RK Jain is grateful to the National Cancer Institute of USA for continuous support of his research on vascular biology since 1980.

Author information

Authors and Affiliations

  1. RK Jain is the Andrew Werk Cook Professor of Radiation Oncology (Tumor Biology) at Harvard Medical School and Director of the Edwin L Steele Laboratory for Tumor Biology in the Department of Radiation Oncology at Massachusetts General Hospital, and HK Gold is Associate Professor of Medicine at Harvard Medical School and an Interventional Cardiologist in the Cardiology Division of the Department of Medicine at the Massachusetts General Hospital, AV Finn is a Cardiology Fellow at the Massachusetts General Hospital, Boston, MA, USA.,

    Rakesh K Jain, Aloke V Finn & Herman K Gold

  2. FD Kolodgie is Associate Director and R Virmani is Medical Director of the CVPath Institute Inc., Gaithersburg, MD, USA.,

    Frank D Kolodgie & Renu Virmani

Authors
  1. Rakesh K Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aloke V Finn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Frank D Kolodgie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Herman K Gold
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Renu Virmani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Rakesh K Jain or Herman K Gold.

Ethics declarations

Competing interests

RK Jain is a consultant for AstraZeneca, Novartis, Pfizer and Thrombogenics. He has received honoraria from Pfizer and Roche, and a grant from AstraZeneca. The other authors declared no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jain, R., Finn, A., Kolodgie, F. et al. Antiangiogenic therapy for normalization of atherosclerotic plaque vasculature: a potential strategy for plaque stabilization. Nat Rev Cardiol 4, 491–502 (2007). https://doi.org/10.1038/ncpcardio0979

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpcardio0979

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing