Angiogenesis

The formation of new blood vessels ÔÇô angiogenesis ÔÇô is a critical condition for growing tissues as this process allows the blood flow necessary for a supply of oxygen and nutrients 1 Pittman RN. Oxygen transport and exchange in the microcirculation. Microcirculation 2005; 12:59-70. . Vascular neoformation is defined differently according to the period or condition in which it arises. During embryogenesis, the term used is vasculogenesis while during the course of physiological events (wound healing, endometrial cycle) the term used is regulated angiogenesis. The term pathological or dysregulation angiogenesis is used in the case of diseases (cancer, rheumatoid arthritis, retinal vascular diseases) 2 Claesson-Welsh L. Blood vessels as targets in tumor therapy. Ups J Med Sci 2012; 117:178-86. . In vasculogenesis, vessels are formed directly from mesodermal angioblastic precursors and this condition may also arise at postnatal age due to the effect of circulatory bone marrow precursors (adult vasculogenesis). In angiogenesis, however, the new vessels are generated from preexisting vessels by a process known as sprouting or by means of a splitting process known as intussusception 3 Burri PH, Hlushchuk R, Djonov V. Intussusceptive angio- genesis: its emergence, its character- istics, and its significance. Dev Dyn. 2004; 231:474-88. 4
Kopp HG, Ramos CA, Rafii S. Contribution of endothelial progenitors and proangiogenic hematopoietic cells to vascularization of tumor and ischemic tissue. Curr Opin Hematol 2006; 13:175ÔÇô81.
. Angiogenesis comes about as a result of the interaction between pro- angiogenic factors and their inhibitors and between them and the extracellular matrix (ECM) 5
Kajdaniuk D, Marek B, Foltyn W, Kos-Kud┼éa B. Vascular endothelial growth factor (VEGF) – part 1: in physiology and pathophysiology. Endokrynol Pol 2011; 62:444-55.
5. Both physiological and pathological angiogenesis are the consequence of pro-angiogenic factors predominating over their inhibitors 6 Kajdaniuk D, Marek B, Foltyn W, Kos-Kud┼éa B. Vascular endothelial growth factor (VEGF) – part 1: in physiology and pathophysiology. Endokrynol Pol 2011; 62:444-55. . Vascular Endothelial Growth Factors (VEGFs) are key molecules in the stimulation of angiogenesis, which is also influenced by other growth factors such as Fibroblast Growth Factors (FGFs), Platelet-Derived Growth Factors (PDGFs), Matrix Metalloproteinases (MMPs) and other cytokines 7 Claesson-Welsh L. Blood vessels as targets in tumor therapy. Ups J Med Sci 2012; 117:178-86. 8 Kajdaniuk D, Marek B, Foltyn W, Kos-Kud┼éa B. Vascular endothelial growth factor (VEGF) – part 1: in physiology and pathophysiology. Endokrynol Pol 2011; 62:444-55. .

Angiogenesis in eye disease

Ocular angiogenesis may bring about irreversible vision impairment due to clouding of the cornea or disruption of the neural structure of the retina. The main conditions of clinical interest involving ocular angiogenesis are: age-related macular degeneration, diabetic retinopathy, corneal neovascularisation and retinopathy of prematurity (ROP). The most important angiogenic factor common to all these condi- tions of the eye is VEGF (for a detailed description of the numerous mediators of ocular angiogenesis, see 9 Qazi Y, Maddula S, Ambati BK. Mediators of ocular angiogenesis. J Genet 2009; 88:495-515. ). VEGF, previously known as Vascular Permeability Factor (VPF), was described for the first time in 1983 by Senger, et al. 10 Senger DR, Galli SJ, Dvorak AM, et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983; 219:983ÔÇô985. . Its genetic coding is located on the short arm of chromosome 6 11 Ferrara N. Vascular endothelial growth factor and the regulation of angiogenesis. Recent Prog Horm Res 2000; 55:15ÔÇô36. . VEGF has a molecular weight of 45 kDa and belongs to the family of PDGFs 12 Leung DW, Cachianes G, Kuang WJ, et al. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989; 246: 306ÔÇô1309. . There are several forms of VEGF known as A, B, C, D 13 Claesson-Welsh L. Blood vessels as targets in tumor therapy. Ups J Med Sci 2012; 117:178-86. : the most common form is A (referred to simply in the literature as VEGF). The biological significance of the other forms is still uncertain. VEGF is the mitogen specific for endothelial cells. It is produced by these cells and secreted by fibroblasts, smooth muscle cells, inflammatory cells, megakaryocytes and numerous other cellular elements 14 Kajdaniuk D, Marek B, Foltyn W, Kos-Kud┼éa B. Vascular endothelial growth factor (VEGF) – part 1: in physiology and pathophysiology. Endokrynol Pol 2011; 62:444-55. . VEGF production is increased during hypoxia 15 Claesson-Welsh L. Blood vessels as targets in tumor therapy. Ups J Med Sci 2012; 117:178-86. . The activity of VEGF depends on the presence of specific receptors on the cell membrane known as VEGFR1, VEGFR2 and VEGFR3 16 Claesson-Welsh L. Blood vessels as targets in tumor therapy. Ups J Med Sci 2012; 117:178-86. . In eye conditions involving angiogenesis, VEGF production is support – ed not only by inflammatory cells and endothelial cells but also by retinal pigment epithelial cells and astrocytes 17
Qazi Y, Maddula S, Ambati BK. Mediators of ocular angiogenesis. J Genet 2009; 88:495-515.
6.

Age-related macular degeneration (AMD)

Throughout the world, AMD is the leading cause of severe vision loss 18 Prokofyeva E, Zrenner E. Epidemiology of major eye diseases leading to blindness in Europe: a literature review. Ophthalmic Res 2012; 47:171-88. . In the USA, this disease is responsible for more than 54% of cases of vision loss in the white population 19 Congdon N, O’Colmain B, Klaver CC, et al. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol. 2004; 122:477-85. . Epidemiological studies indicate that more than 1 million Americans are affected by the neovascular form (see below) and 970,000 are affected by the atrophic form (see below) 20 Friedman DS, O’Colmain BJ, Mu├▒oz B, et al. Prevalence of age-related macular degenera- tion in the United States. Arch Ophthalmol. 2004; 122:564-72. . A recent review of the literature shows that in Europe the overall prevalence of AMD in people aged 65-75 years varies from 9 to 25% 21 Prokofyeva E, Zrenner E. Epidemiology of major eye diseases leading to blindness in Europe: a literature review. Ophthalmic Res 2012; 47:171-88. . France and Germany are the countries with the highest prevalence, 40 and 39% respectively, while in the United Kingdom the prevalence is 3.5% 22 Prokofyeva E, Zrenner E. Epidemiology of major eye diseases leading to blindness in Europe: a literature review. Ophthalmic Res 2012; 47:171-88. ┬á. In Italy it is estimated that 1 million people show signs of AMD. Every year, 20,000 new cases of the neovascular form (see below) are record ed, which strike one percent of the over 50s, 14% of the over 75s and 30% of the over 85s. Blindness occurs in old age: more than 80% of those affected become blind after the age of 70 23 Gohdes DM, Balamurugan A, Larsen BA, Maylahn C. Age-related eye diseases: an emerg- ing challenge for public health professionals. Prev Chronic Dis. 2005; 2:A17. . AMD is twice as common in women as in men 24 Coleman HR, Chan CC, Ferris FL 3rd, Chew EY. Age-related macular degeneration. Lancet. 2008; 372:1835-45. . The exact pathogenesis of this disease remains unclear. It is a multi- factorial disease related to the interaction of genetic and environmental factors 25 Liutkeviciene R, Lesauskaite V, Asmoniene V, et al. Factors determining age-related mac- ular degeneration: a current view. Medicina (Kaunas). 2010; 46:89-94. . Cigarette smoking is prominent among these 26 Coleman HR, Chan CC, Ferris FL 3rd, Chew EY. Age-related macular degeneration. Lancet. 2008; 372:1835-45. . Smoking acts through oxidative stress, which is considered one of the main mechanisms influencing the onset of AMD 27 Beatty S, Koh H, Phil M, Henson D, Boulton M. The role of oxidative stress in the pathogen- esis of age-related macular degeneration. Surv Ophthalmol 2000; 45:115ÔÇô134 28 Sarangarajan R, Apte SP. Melanin aggregation and polymerization: possible implications in age-related macular degeneration. Ophthalmic Res. 2005; 37:136-41. . AMD can occur in two forms: dry (non-exudative or atrophic) and wet (exudative or neurovascular). The dry form is characterised by the appearance of drusen in the retina: this is an accumulation of hyaline material (lipids, phospholi- pids and collagen) that is deposited in Bruch’s membrane underlying the retinal pigmented epithelium. The drusen deposits hinder oxygen ation and bring about the degeneration of photoreceptors, with atrophy and a gradual reduction in acuity 29 Liutkeviciene R, Lesauskaite V, Asmoniene V, et al. Factors determining age-related mac- ular degeneration: a current view. Medicina (Kaunas). 2010; 46:89-94. . It has been shown that more than 8 million Americans have at least one large drusen in one eye and that drusen are present on both sides in 3.6 million of these cases 30 Friedman DS, O’Colmain BJ, Mu├▒oz B, et al. Prevalence of age-related macular degenera- tion in the United States. Arch Ophthalmol. 2004; 122:564-72. . It is very important to note that the dry form can evolve into the more severe wet form. The wet form includes exudation and macular bleeding, generated by the choroid neoangiogenesis, which gives rise to rapid vision loss. The standard treatment for neurovascular AMD is intravitreal injection of an anti-VEGF drug 31 Noble J, Chaudhary V. Age-related macular degeneration. CMAJ 2010; 182:1759. .

Proliferative diabetic retinopathy

This is one of the most dangerous complications of diabetes mellitus, which causes blindness in some 2.4 million people throughout the world 32 Prokofyeva E, Zrenner E. Epidemiology of major eye diseases leading to blindness in Europe: a literature review. Ophthalmic Res 2012; 47:171-88. . In the early stages of the disease, a thickening of the capillary basement membrane can be observed histologically with loss of endothelial cells and pericytes. The advanced stages are characterised by the appearance of neo-angiogenesis resulting in oedema and retinal disruption 33 Qazi Y, Maddula S, Ambati BK. Mediators of ocular angiogenesis. J Genet 2009; 88:495-515. . This is due to chronic hyperglycaemia, which causes oxidat ive stress, the formation of microthrombi, leukostasis and cyto – kine activation. The consequent ischaemia causes the overexpression of cytokines and growth factors, first and foremost VEGF 34 Qazi Y, Maddula S, Ambati BK. Mediators of ocular angiogenesis. J Genet 2009; 88:495-515. . Treatment is based on the use of an anti-VEGF agent 35 Brandt CS. Management of retinal vascular diseases: a patient-centric approach. Eye. 2012; 26:S1-S16. Lycopene: new therapeutic approach in retinal neovascularisation .

Corneal neovascularisation

Corneal neovascularisation is a severe condition that can cause marked vision impairment. Under physiological conditions, the cornea maintains a process of avascularity known as ÔÇ£angiogenic privilegeÔÇØ in order to allow a maximum amount of incident light to pass through. Corneal neovascularisation occurs when the delicate balance between anti-angiogenic and angiogenic factors shifts in favour of the latter 36 Chang JH, Garg NK, Lunde E, et al. Corneal neovascularization: an anti-VEGF therapy re- view. Surv Ophthalmol. 2012; 57:415-29. . This happens as a result of chemical, mechanical, infectious and degenerative insults that trigger an inflammatory process, which in turn up-regulates the expression of angiogenesis mediators 37 Sarangarajan R, Apte SP. Melanin aggregation and polymerization: possible implications in age-related macular degeneration. Ophthalmic Res. 2005; 37:136-41. . In corneal neovascularisation, the new vessels originate from the pericorneal lexis and spread throughout the stroma 38
Qazi Y, Maddula S, Ambati BK. Mediators of ocular angiogenesis. J Genet 2009; 88:495-515.
6. Treatment involves the use of anti- VEGF drugs 39 Chang JH, Garg NK, Lunde E, et al. Corneal neovascularization: an anti-VEGF therapy re- view. Surv Ophthalmol. 2012; 57:415-29. .

Retinopathy of prematurity

ROP is the main cause of blindness in children. The most important pathological aspect of this condition is abnormal retinal angio- genesis. In the premature infant, pathological neovascularisation is de- termined by a rise in VEGF under conditions of retinal tissue hypoxia 40 Niranjan HS, Benakappa N, Reddy KB, et al. Retinopathy of prematurity promising newer modalities of treatment. Indian Pediatr. 2012; 49:139-43. . The target of retinopathy of prematurity treatment is the VEGF and there are two possible approaches: laser ablation of the avascular peripheral retina producing this factor and the use of anti-VEGF agents 41 Niranjan HS, Benakappa N, Reddy KB, et al. Retinopathy of prematurity promising newer modalities of treatment. Indian Pediatr. 2012; 49:139-43. .

AMD, anti-angiogenesis and lycopene

Inhibition of angiogenesis is now a therapeutic strategy in the prevention and treatment of several human diseases. Researchers have focused their attention on angiogenesis in the course of malignancies but, as previously described, neovascularisation repre- sents an important stage in the development of serious eye conditions. To prevent and counter angiogenesis in the eye, it is necessary to identify and use angiostatic molecules with little or no toxicity and a route of administration that is as simple as possible. Very recent studies have shown that lycopene displays very strong anti-angiogenic activity as well as being a potent antioxidant. Sahin, et al. 42 Sahin M, Sahin E, Gümüşlü S. Effects of lycopene and apigenin on human umbilical vein en- dothelial cells in vitro under angiogenic stimulation. Acta Histochem. 2012; 114:94-100. , using human endothelial cells, showed that lycopene reduces their proliferation, their migration and the formation of new cap illaries in vitro in a dose-dependent manner (Figure 1).

Inhibition of angiogenesis has been confirmed by other studies 43 Chang JH, Garg NK, Lunde E, et al. Corneal neovascularization: an anti-VEGF therapy re- view. Surv Ophthalmol. 2012; 57:415-29. 44 Niranjan HS, Benakappa N, Reddy KB, et al. Retinopathy of prematurity promising newer modalities of treatment. Indian Pediatr. 2012; 49:139-43. 45 Sahin M, Sahin E, Gümüşlü S. Effects of lycopene and apigenin on human umbilical vein en- dothelial cells in vitro under angiogenic stimulation. Acta Histochem. 2012; 114:94-100. , which showed that this effect is the result of various mechanisms:

anti-VEGF activity 46 Elgass S, Cooper A, Chopra M. Lycopene inhibits angiogenesis in human umbilical vein en- dothelial cells and rat aortic rings. Br J Nutr. 2012; 108:431-9. ; anti TNF-╬▒ action (pro-angiogenic cytokine) 47 Elgass S, Cooper A, Chopra M. Lycopene inhibits angiogenesis in human umbilical vein en- dothelial cells and rat aortic rings. Br J Nutr. 2012; 108:431-9 ; up-regulation of IL-12 and IFN-╬│ (anti-angiogenic cytokines) 48 Huang CS, Chuang CH, Lo TF, Hu ML. Anti-angiogenic effects of lycopene through im- munomodualtion of cytokine secretion in human peripheral blood mononuclear cells. J Nutr Biochem. 2012 Jun 14. ; Inhibition of MMP-2 (pro-angiogenic protease) via attenuation of VEGFR2 49 Chen ML, Lin YH, Yang CM, Hu ML. Lycopene inhibits angiogenesis both in vitro and in vivo by inhibiting MMP-2/uPA system through VEGFR2-mediated PI3K-Akt and ERK/p38 signaling pathways. Mol Nutr Food Res. 2012; 56:889-99. .

It has been stressed that lycopene exerts its antiangiogenic effect at con- centrations that can also be achieved in vivo but because of variability between individuals and the content of lycopene in tomatoes, it is not yet possible to indicate the amount of these vegetables necessary to achieve the purpose 50 Elgass S, Cooper A, Chopra M. Lycopene inhibits angiogenesis in human umbilical vein en- dothelial cells and rat aortic rings. Br J Nutr. 2012; 108:431-9. . Though it has long been known that lycopene levels are lower in patients with AMD 51 Mares-Perlman JA, Brady WE, Klein R, et al. Serum antioxidants and age-related macular degeneration in a population-based case-control study. Arch Ophthalmol. 1995; 113:1518-23. , an inverse correlation has only recently been ob served between plasma levels of carotenoids and the presence of this serious eye disease. This is particularly important for lycopene (Figure 2), which has been null

found to be the only carotenoid able to offer significant protection against the initial form and to an even greater extent against the wet form (Figure 3) 52 Zhou H, Zhao X, Johnson EJ, et al. Serum carotenoids and risk of age-related macular de- generation in a chinese population sample. Invest Ophthalmol Vis Sci. 2011; 52:4338-44. .

Level of protection against AMD exercised by lycopene 53
Huang CS, Chuang CH, Lo TF, Hu ML. Anti-angiogenic effects of lycopene through im- munomodualtion of cytokine secretion in human peripheral blood mononuclear cells. J Nutr Biochem. 2012 Jun 14.

Conclusions

Pathological angiogenesis is a worrying event that occurs in various eye diseases, AMD first and foremost. In this disease, plasma levels of lycopene are reduced and this has been found to be the only carotenoid able to protect against both the initial and the wet form. The mechanism of action through which lycopene exercises this protection may be explained by its high antioxidant properties and its proven antiangiogenic activity. These findings suggest that this carotenoid is an effective aid in the prevention and treatment of AMD.


References   [ + ]

1. Pittman RN. Oxygen transport and exchange in the microcirculation. Microcirculation 2005; 12:59-70.
2, 7, 13, 15, 16. Claesson-Welsh L. Blood vessels as targets in tumor therapy. Ups J Med Sci 2012; 117:178-86.
3. Burri PH, Hlushchuk R, Djonov V. Intussusceptive angio- genesis: its emergence, its character- istics, and its significance. Dev Dyn. 2004; 231:474-88.
4.
Kopp HG, Ramos CA, Rafii S. Contribution of endothelial progenitors and proangiogenic hematopoietic cells to vascularization of tumor and ischemic tissue. Curr Opin Hematol 2006; 13:175ÔÇô81.
5.
Kajdaniuk D, Marek B, Foltyn W, Kos-Kud┼éa B. Vascular endothelial growth factor (VEGF) – part 1: in physiology and pathophysiology. Endokrynol Pol 2011; 62:444-55.
6. Kajdaniuk D, Marek B, Foltyn W, Kos-Kud┼éa B. Vascular endothelial growth factor (VEGF) – part 1: in physiology and pathophysiology. Endokrynol Pol 2011; 62:444-55.
8, 14. Kajdaniuk D, Marek B, Foltyn W, Kos-Kud┼éa B. Vascular endothelial growth factor (VEGF) – part 1: in physiology and pathophysiology. Endokrynol Pol 2011; 62:444-55.
9. Qazi Y, Maddula S, Ambati BK. Mediators of ocular angiogenesis. J Genet 2009; 88:495-515.
10. Senger DR, Galli SJ, Dvorak AM, et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983; 219:983ÔÇô985.
11. Ferrara N. Vascular endothelial growth factor and the regulation of angiogenesis. Recent Prog Horm Res 2000; 55:15ÔÇô36.
12. Leung DW, Cachianes G, Kuang WJ, et al. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989; 246: 306ÔÇô1309.
17, 38.
Qazi Y, Maddula S, Ambati BK. Mediators of ocular angiogenesis. J Genet 2009; 88:495-515.
18, 21, 22, 32. Prokofyeva E, Zrenner E. Epidemiology of major eye diseases leading to blindness in Europe: a literature review. Ophthalmic Res 2012; 47:171-88.
19. Congdon N, O’Colmain B, Klaver CC, et al. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol. 2004; 122:477-85.
20, 30. Friedman DS, O’Colmain BJ, Mu├▒oz B, et al. Prevalence of age-related macular degenera- tion in the United States. Arch Ophthalmol. 2004; 122:564-72.
23. Gohdes DM, Balamurugan A, Larsen BA, Maylahn C. Age-related eye diseases: an emerg- ing challenge for public health professionals. Prev Chronic Dis. 2005; 2:A17.
24. Coleman HR, Chan CC, Ferris FL 3rd, Chew EY. Age-related macular degeneration. Lancet. 2008; 372:1835-45.
25. Liutkeviciene R, Lesauskaite V, Asmoniene V, et al. Factors determining age-related mac- ular degeneration: a current view. Medicina (Kaunas). 2010; 46:89-94.
26. Coleman HR, Chan CC, Ferris FL 3rd, Chew EY. Age-related macular degeneration. Lancet. 2008; 372:1835-45.
27. Beatty S, Koh H, Phil M, Henson D, Boulton M. The role of oxidative stress in the pathogen- esis of age-related macular degeneration. Surv Ophthalmol 2000; 45:115ÔÇô134
28, 37. Sarangarajan R, Apte SP. Melanin aggregation and polymerization: possible implications in age-related macular degeneration. Ophthalmic Res. 2005; 37:136-41.
29. Liutkeviciene R, Lesauskaite V, Asmoniene V, et al. Factors determining age-related mac- ular degeneration: a current view. Medicina (Kaunas). 2010; 46:89-94.
31. Noble J, Chaudhary V. Age-related macular degeneration. CMAJ 2010; 182:1759.
33, 34. Qazi Y, Maddula S, Ambati BK. Mediators of ocular angiogenesis. J Genet 2009; 88:495-515.
35. Brandt CS. Management of retinal vascular diseases: a patient-centric approach. Eye. 2012; 26:S1-S16. Lycopene: new therapeutic approach in retinal neovascularisation
36, 39, 43. Chang JH, Garg NK, Lunde E, et al. Corneal neovascularization: an anti-VEGF therapy re- view. Surv Ophthalmol. 2012; 57:415-29.
40, 41, 44. Niranjan HS, Benakappa N, Reddy KB, et al. Retinopathy of prematurity promising newer modalities of treatment. Indian Pediatr. 2012; 49:139-43.
42. Sahin M, Sahin E, Gümüşlü S. Effects of lycopene and apigenin on human umbilical vein en- dothelial cells in vitro under angiogenic stimulation. Acta Histochem. 2012; 114:94-100.
45. Sahin M, Sahin E, Gümüşlü S. Effects of lycopene and apigenin on human umbilical vein en- dothelial cells in vitro under angiogenic stimulation. Acta Histochem. 2012; 114:94-100.
46, 50. Elgass S, Cooper A, Chopra M. Lycopene inhibits angiogenesis in human umbilical vein en- dothelial cells and rat aortic rings. Br J Nutr. 2012; 108:431-9.
47. Elgass S, Cooper A, Chopra M. Lycopene inhibits angiogenesis in human umbilical vein en- dothelial cells and rat aortic rings. Br J Nutr. 2012; 108:431-9
48. Huang CS, Chuang CH, Lo TF, Hu ML. Anti-angiogenic effects of lycopene through im- munomodualtion of cytokine secretion in human peripheral blood mononuclear cells. J Nutr Biochem. 2012 Jun 14.
49. Chen ML, Lin YH, Yang CM, Hu ML. Lycopene inhibits angiogenesis both in vitro and in vivo by inhibiting MMP-2/uPA system through VEGFR2-mediated PI3K-Akt and ERK/p38 signaling pathways. Mol Nutr Food Res. 2012; 56:889-99.
51. Mares-Perlman JA, Brady WE, Klein R, et al. Serum antioxidants and age-related macular degeneration in a population-based case-control study. Arch Ophthalmol. 1995; 113:1518-23.
52. Zhou H, Zhao X, Johnson EJ, et al. Serum carotenoids and risk of age-related macular de- generation in a chinese population sample. Invest Ophthalmol Vis Sci. 2011; 52:4338-44.
53.
Huang CS, Chuang CH, Lo TF, Hu ML. Anti-angiogenic effects of lycopene through im- munomodualtion of cytokine secretion in human peripheral blood mononuclear cells. J Nutr Biochem. 2012 Jun 14.