Skip to main content
SpringerLink
Log in

Angiogenesis in Atherosclerosis: An Overview

  • Chapter
  • First Online:
Biochemical Basis and Therapeutic Implications of Angiogenesis

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 6))

Abstract

Angiogenesis, the process of formation of new blood vessels, involves a complex interplay of various growth signals and cellular milieu. It plays an important role in many physiological and pathological processes. The study of angiogenesis has gained momentum from two different perspectives. On the one hand, angiogenesis is essential for physiologic processes such as menstrual bleeding, wound healing, and embryonic development; on the other hand, histopathologic studies suggest that angiogenesis has an important role in the growth of the atherosclerotic plaque and several tumors. From a clinical perspective, drugs that inhibit angiogenesis seem to increase the incidence of thromboembolic events. Recent data suggests that endothelial-derived growth factor (VEGF) constitutes only a small proportion of total body VEGF and does not contribute significantly to the overall angiogenic response. However, such autocrine VEGF signaling is required for endothelial cell survival and maintenance of vascular homeostasis. In parallel, the discovery of VEGF has guided us to therapeutic angiogenesis as a possible treatment for ischemic heart and peripheral disease. Results of numerous preclinical studies have provided evidence that angiogenic growth factors can promote collateral channel development which can reduce ischemia. Nonetheless, clinical trials on therapeutic angiogenesis have not been very impressive as expected. Bench and bedside research continues to bring insight into the mechanisms of tissue ischemia and tumor growth. Further understanding of different facets of angiogenesis may help in the development of novel and specific therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 179.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Risau W (1997) Mechanisms of angiogenesis. Nature 386:671–674

    Article  PubMed  CAS  Google Scholar 

  2. Schaper W, Scholz D (2003) Factors regulating arteriogenesis. Arterioscler Thromb Vasc Biol 23:1143–1151

    Article  PubMed  CAS  Google Scholar 

  3. Takahashi H, Shibuya M (2005) The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. Clin Sci 109:227–241

    Article  PubMed  CAS  Google Scholar 

  4. Koch S, Tugues S, Li X, Gualandi L, Claesson-Welsh L (2011) Signal transduction by vascular endothelial growth factor receptors. Biochem J 437:169–183

    Article  PubMed  CAS  Google Scholar 

  5. Carmeliet P (2000) Mechanisms of angiogenesis and arteriogenesis. Nat Med 6:389–395

    Article  PubMed  CAS  Google Scholar 

  6. Sluimer JC, Daemen MJ (2009) Novel concepts in atherogenesis: angiogenesis and hypoxia in atherosclerosis. J Pathol 218:7–29

    Article  PubMed  Google Scholar 

  7. Ago T, Kuroda J, Kamouchi M et al (2011) Pathophysiological roles of NADPH oxidase/nox family proteins in the vascular system. -Review and perspective-. Circ J 75:1791–1800

    Article  PubMed  CAS  Google Scholar 

  8. Jiang J, Yan M, Mehta JL, Hu C (2011) Angiogenesis is a link between atherosclerosis and tumorigenesis: role of LOX-1. Cardiovasc Drugs Ther 25:461–468

    Article  PubMed  CAS  Google Scholar 

  9. Li D, Mehta JL (2000) Upregulation of endothelial receptor for oxidized LDL (LOX-1) by oxidized LDL and implications in apoptosis of human coronary artery endothelial cells: evidence from use of antisense LOX-1 mRNA and chemical inhibitors. Arterioscler Thromb Vasc Biol 20:1116–1122

    Article  PubMed  CAS  Google Scholar 

  10. Dandapat A, Hu C, Sun L, Mehta JL (2007) Small concentrations of oxLDL induce capillary tube formation from endothelial cells via LOX-1-dependent redox-sensitive pathway. Arterioscler Thromb Vasc Biol 27:2435–2442

    Article  PubMed  CAS  Google Scholar 

  11. Kanata S, Akagi M, Nishimura S et al (2006) Oxidized LDL binding to LOX-1 upregulates VEGF expression in cultured bovine chondrocytes through activation of PPAR-gamma. Biochem Biophys Res Commun 348:1003–1010

    Article  PubMed  CAS  Google Scholar 

  12. Hu C, Dandapat A, Mehta JL (2007) Angiotensin II induces capillary formation from endothelial cells via the LOX-1 dependent redox-sensitive pathway. Hypertension 50:952–957

    Article  PubMed  CAS  Google Scholar 

  13. Khaidakov M, Szwedo J, Mitra S et al (2010) Antiangiogenic and antimitotic effects of aspirin in hypoxia-reoxygenation modulation of the LOX-1-NADPH oxidase axis as a potential mechanism. J Cardiovasc Pharmacol 56:635–641

    Article  PubMed  CAS  Google Scholar 

  14. Koester W (1876) Endareritis and arteritis. Berl Klin Wochenschr 13:454–455

    Google Scholar 

  15. Winternitz MC, Thomas RM, LeCompte PM (1938) The biology of arteriosclerosis. C.C. Thomas, Springfield

    Google Scholar 

  16. Wilens SL, Plair CM (1965) Blood cholesterol, nutrition, atherosclerosis. A necropsy study. Arch Intern Med 116:373–380

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  18. Kolodgie FD, Virmani R, Burke AP et al (2004) Pathologic assessment of the vulnerable human coronary plaque. Heart 90:1385–1391

    Article  PubMed  CAS  Google Scholar 

  19. Barger AC, Beeuwkes R III (1990) Rupture of coronary vasa vasorum as a trigger of acute myocardial infarction. Am J Cardiol 66:41–43

    Article  Google Scholar 

  20. Moulton KS, Heller E, Konerding MA 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  PubMed  CAS  Google Scholar 

  21. Moulton KS, Vakili K, Zurakowski D et al (2003) Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis. Proc Natl Acad Sci U S A 100:4736–4741

    Article  PubMed  CAS  Google Scholar 

  22. Celletti FL, Waugh JM, Amabile PG, Brendolan A, Hilfiker PR, Dake MD (2001) Vascular endothelial growth factor enhances atherosclerotic plaque progression. Nat Med 7:425–429

    Article  PubMed  CAS  Google Scholar 

  23. Khurana R, Zhuang Z, Bhardwaj S et al (2004) Angiogenesis-dependent and independent phases of intimal hyperplasia. Circulation 110:2436–2443

    Article  PubMed  Google Scholar 

  24. Zhao Q, Egashira K, Hiasa K et al (2004) Essential role of vascular endothelial growth factor and Flt-1 signals in neointimal formation after periadventitial injury. Arterioscler Thromb Vasc Biol 24:2284–2289

    Article  PubMed  CAS  Google Scholar 

  25. Barger AC, Beeuwkes R III, Lainey LL, Silverman KJ (1984) Hypothesis: vasa vasorum and neovascularization of human coronary arteries: a possible role in the pathophysiology of atherosclerosis. N Engl J Med 310:175–177

    Article  PubMed  CAS  Google Scholar 

  26. Mofidi R, Crotty TB, McCarthy P et al (2001) Association between plaque instability, angiogenesis and symptomatic carotid occlusive disease. Br J Surg 88:945–950

    Article  PubMed  CAS  Google Scholar 

  27. Hiyama T, Tanaka T, Endo S et al (2010) Angiogenesis in atherosclerotic plaque obtained from carotid endarterectomy: association between symptomatology and plaque morphology. Neurol Med Chir 50:1056–1061

    Article  Google Scholar 

  28. Aiello LP, Avery RL, Arrigg PG et al (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331:1480–1487

    Article  PubMed  CAS  Google Scholar 

  29. Kakehashi A, Inoda S, Mameuda C, Kuroki M et al (2008) Relationship among VEGF, VEGF receptor, AGEs, and macrophages in proliferative diabetic retinopathy. Diabetes Res Clin Pract 79:438–445

    Article  PubMed  CAS  Google Scholar 

  30. Nalluri SR, Chu D, Keresztes R, Zhu X, Wu S (2008) Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA 300:2277–2285

    Article  PubMed  CAS  Google Scholar 

  31. Ranpura V, Hapani S, Chuang J, Wu S (2010) Risk of cardiac ischemia and arterial thromboembolic events with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-­analysis of randomized controlled trials. Acta Oncol 49:287–297

    Article  PubMed  CAS  Google Scholar 

  32. Daher IN, Yeh ET (2008) Vascular complications of selected cancer therapies. Nat Clin Pract Cardiovasc Med 5:797–805

    Article  PubMed  CAS  Google Scholar 

  33. Menon SP, Rajkumar SV, Lacy M, Falco P, Palumbo A (2008) Thromboembolic events with lenalidomide-based therapy for multiple myeloma. Cancer 112:1522–1528

    Article  PubMed  CAS  Google Scholar 

  34. Sugimoto H, Hamano Y, Charytan D et al (2003) Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria. J Biol Chem 278:12605–12608

    Article  PubMed  CAS  Google Scholar 

  35. Lee S, Chen TT, Barber CL et al (2007) Autocrine VEGF signaling is required for vascular homeostasis. Cell 130:691–703

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  37. Izumiya Y, Shiojima I, Sato K et al (2006) Vascular endothelial growth factor blockade promotes the transition from compensatory cardiac hypertrophy to failure in response to pressure overload. Hypertension 47:887–993

    Article  PubMed  CAS  Google Scholar 

  38. Van Royen N, Piek JJ, Schaper W et al (2001) Arteriogenesis: mechanisms and modulation of collateral artery development. J Nucl Cardiol 8:687–693

    Article  PubMed  Google Scholar 

  39. Chen CH, Walterscheid JP (2006) Plaque angiogenesis versus compensatory arteriogenesis in atherosclerosis. Circ Res 99:787–789

    Article  PubMed  CAS  Google Scholar 

  40. Ribatti D, Nico B, Vacca A, Roncali L, Dammacco F (2002) Endothelial cell heterogeneity and organ specificity. J Hematother Stem Cell Res 11:81–90

    Article  PubMed  Google Scholar 

  41. Owman C, Hardebo JE (1988) Functional heterogeneity of cerebrovascular endothelium. Brain Behav Evol 32:65–75

    Article  PubMed  CAS  Google Scholar 

  42. Auerbach R (1992) Endothelial cell heterogeneity: its role as a determinant of selective metastasis. In: Simionescu N, Simionescu M (eds) Endothelial cell dysfunctions. Plenum Press, New York, pp 427–437

    Google Scholar 

  43. Belloni PN, Carney DH, Nicolson GL (1992) Organ-derived microvessel endothelial cells exhibit differential responsiveness to thrombin and other growth factors. Microvasc Res 43:20–45

    Article  PubMed  CAS  Google Scholar 

  44. Chi JT, Chang HY, Haraldsen G, Jahnsen FL et al (2003) Endothelial cell diversity revealed by global expression profiling. Proc Natl Acad Sci U S A 100:10623–10628

    Article  PubMed  CAS  Google Scholar 

  45. Deng D, Tsalenko A, Vailaya A et al (2006) Differences in vascular bed disease susceptibility reflect differences in gene expression response to atherogenic stimuli. Circ Res 98:200–208

    Article  PubMed  CAS  Google Scholar 

  46. Page C, Rose M, Yacoub M, Pigott R (1991) Antigenic heterogeneity of vascular endothelium. Am J Pathol 141:677–683

    Google Scholar 

  47. Aird WC, Edelberg JM, Weiler-Guettler H et al (1997) Vascular bed-specific expression of an endothelial cell is programmed by the tissue microenvironment. J Cell Biol 138:1117–1124

    Article  PubMed  CAS  Google Scholar 

  48. Pettersson A, Nagy JA, Brown LF, Sundberg C, Morgan E et al (2000) Heterogeneity of the angiogenic response induced in different normal adult tissues by vascular permeability factor/vascular endothelial growth factor. Lab Invest 80:99–115

    Article  PubMed  CAS  Google Scholar 

  49. Simpson E, Linder CC, Sargent EE, Davisson MT, Mobraaten LE, Sharp JJ (1997) Genetic variation among 129 substrains and its importance for targeted mutagenesis in mice. Nat Genet 16:19–27

    Article  PubMed  CAS  Google Scholar 

  50. Griep AE, Krawcek J, Lee D et al (1998) Multiple genetic loci modify risk for retinoblastoma in transgenic mice. Invest Ophthalmol Vis Sci 39:2723–2732

    PubMed  CAS  Google Scholar 

  51. Thurston G, Murphy T, Baluk P, Lindsey JR, MacDonald DM (1998) Angiogenesis in mice with chronic airway inflammation: strain-dependent differences. Am J Pathol 153:1099–1112

    Article  PubMed  CAS  Google Scholar 

  52. Rohan RM, Fernandez A, Udagawa T, Yuan J, D’Amato RJ (2000) Genetic heterogeneity of angiogenesis in mice. FASEB J 14:871–876

    PubMed  CAS  Google Scholar 

  53. Roger VL, Go AS, Lloyd-Jones DM et al (2012) Heart disease and stroke statistics–2012 update: a report from the American Heart Association. Circulation 125:e2–e220

    Article  PubMed  Google Scholar 

  54. Ware JA, Simons M (1997) Angiogenesis in ischemic heart disease. Nat Med 3:158–164

    Article  PubMed  CAS  Google Scholar 

  55. Zachary I, Morgan RD (2011) Therapeutic angiogenesis for cardiovascular disease: biological context, challenges, prospects. Heart 97:181–189

    Article  PubMed  CAS  Google Scholar 

  56. Henry TD, Annex BH, McKendall GR et al (2003) The VIVA trial: vascular endothelial growth factor in ischemia for vascular angiogenesis. Circulation 107:1359–1365

    Article  PubMed  CAS  Google Scholar 

  57. Simons M, Annex BH, Laham RJ et al (2002) Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2: double-blind, randomized, controlled clinical trial. Circulation 105:788–793

    Article  PubMed  CAS  Google Scholar 

  58. Hedman M, Hartikainen J, Syvänne M et al (2003) Safety and feasibility of catheter-based local intracoronary vascular endothelial growth factor gene transfer in the prevention of postangioplasty and in-stent restenosis and in the treatment of chronic myocardial ischemia: phase II results of the Kuopio Angiogenesis Trial (KAT). Circulation 107:2677–2683

    Article  PubMed  CAS  Google Scholar 

  59. Kastrup J, Jørgensen E, Rück A et al (2005) Direct intramyocardial plasmid vascular endothelial growth factor-A165 gene therapy in patients with stable severe angina pectoris. A randomized double-blind placebo-controlled study: the Euroinject One trial. J Am Coll Cardiol 45:982–988

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of Interest

None

Disclosures  None

Author information

Authors and Affiliations

  1. Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, 4301 West Markham, Little Rock, AR, 72205, USA

    Sadip Pant, Abhishek Deshmukh & Jawahar L. Mehta

Authors
  1. Sadip Pant
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Abhishek Deshmukh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jawahar L. Mehta
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jawahar L. Mehta .

Editor information

Editors and Affiliations

  1. Div. of Cardiovascular Medicine, UAMS, Little Rock, AR, USA, 4301 W Markham, Little Rock, 72205, Arkansas, USA

    Jawahar L. Mehta

  2. Institute of Cardiovascular Sciences, St. Boniface Hosp. Research, Univ. of Ma, 351 Tache Avenue, Winnipeg, R2H 2A6, Manitoba, Canada

    Naranjan S. Dhalla

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Pant, S., Deshmukh, A., Mehta, J.L. (2013). Angiogenesis in Atherosclerosis: An Overview. In: Mehta, J., Dhalla, N. (eds) Biochemical Basis and Therapeutic Implications of Angiogenesis. Advances in Biochemistry in Health and Disease, vol 6. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5857-9_12

Download citation

Publish with us

Policies and ethics

Search

Navigation