**Author details**

#### Sepehr Feizi

neal angiogenesis more effectively than bevacizumab [66]. Subconjunctival ranibizumab sig‐ nificantly reduces VEGF levels not only in the bulbar conjunctiva and cornea but also in the iris and aqueous humor [67]. Clinically, stable corneal neovascularization can be effectively treated by topical ranibizumab 1% as evidenced by a significant reduction in vessel caliber and neovascular area with no significant change in invasion area. These findings suggest that the main outcome of ranibizumab treatment for stable corneal neovascularization is to induce

PEDF is a glycoprotein with neurotrophic, antitumorigenic, and antiangiogenic functions. PEDF can inhibit FGF, VEGF, and interlukin‐8 (IL‐8/CXCL8)‐mediated angiogenesis by inducing the cells' apoptosis and reducing endothelial cell migration simultaneously [68, 69]. It is also found to play an important role in the antiangiogenic effect of AMT [70]. Topical PEDF or PEDF‐derived (P5‐2 and P5‐3) peptides can downregulate VEGF expression and

Anti‐VEGF antibodies block the effect of VEGF before it attaches to the endothelial recep‐ tors. Tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2) that is predominantly or exclusively expressed in endothelial cells is an important regulator of angiogenesis. Tyrosine kinase inhibitors inhibit the activity of VEGF by block‐ ing tyrosine kinase in the intracellular part of the VEGF cell membrane receptor. This may offer a different opportunity for the management of the angiogenesis process in corneal dis‐ eases. Regorafenib is a multikinase inhibitor that targets various kinases, including PDGF β, VEGFR1, VEGFR2, and VEGFR3, mutant oncogenic kinases, TIE2, and the FGF receptor, which are involved in neovascularization. The inhibitory effects of topical regorafenib are comparable to those of topical bevacizumab and dexamethasone [72]. Sunitinib is a multitar‐ geted receptor tyrosine kinase inhibitor that blocks both VEGF and PDGF. Topically adminis‐ tered sunitinib can reduce corneal neovascularization more effectively than bevacizumab [73]. Trastuzumab is a monoclonal antibody that interferes with the HER2/ neu receptor. Lapatinib is a dual tyrosine kinase inhibitor, which interrupts the epidermal growth factor receptor (EGFR) and HER2/ neu pathways. Lapatinib used in the form of lapatinib ditosylate is an orally active drug for solid tumors such as breast cancer. In recent studies, both substances were compared for the treatment of experimental corneal angiogenesis. The results suggested that systemically administered lapatinib is more effective than systemically administered

Corneal neovascularization is a common clinical feature in different corneal diseases includ‐ ing ocular traumatic or chemical injury, autoimmune diseases, chronic contact lens wear, infectious keratitis, and keratoplasties. Although corneal neovascularization can serve a

inhibit corneal neovascularization in a chemical‐induced corneal model [71].

the narrowing of vessels more than a reduction in their length.

70 Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

trastuzumab in preventing corneal angiogenesis [74].

**7. Conclusion**

*6.4.2. Pigment epithelium‐derived factor*

*6.4.3. Tyrosine kinase inhibitors*

Address all correspondence to: sepehrfeizi@yahoo.com

Ophthalmic Research Center and Department of Ophthalmology, Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

## **References**


[24] Goldman J, Rutkowski JM, Shields JD, Pasquier MC, Cui Y, Schmökel HG, Willey S, Hicklin DJ, Pytowski B, Swartz MA. Cooperative and redundant roles of VEGFR‐2 and VEGFR‐3 signaling in adult lymphangiogenesis. FASEB J 2007;21(4):1003–1012.

[9] Tshionyi M, Shay E, Lunde E, Lin A, Han KY, Jain S, Chang JH, Azar DT. Hemangiogenesis

[10] Beebe DC. Maintaining transparency: a review of the developmental physiology and pathophysiology of two avascular tissues. Semin Cell Dev Biol 2008;19(2):125–133. [11] Madigan MC, Penfold PL, Holden BA, Billson FA. Ultrastructural features of con‐ tact lens‐induced deep corneal neovascularization and associated stromal leukocytes.

[12] Wong AL, Weissman BA, Mondino BJ. Bilateral corneal neovascularization and opacification associated with unmonitored contact lens wear. Am J Ophthalmol

[13] Remeijer L, Duan R, van Dun JM, Wefers Bettink MA, Osterhaus AD, Verjans GM. Prevalence and clinical consequences of herpes simplex virus type 1 DNA in human

[14] Hayashi K, Hooper LC, Detrick B, Hooks JJ. HSV immune complex (HSV‐IgG: IC) and HSV‐DNA elicit the production of angiogenic factor VEGF and MMP‐9. Arch Virol

[15] Dua HS, Azuara‐Blanco A. Limbal stem cells of the corneal epithelium. Surv Ophthalmol

[16] Kokotas H, Petersen MB. Clinical and molecular aspects of aniridia. Clin Genet

[17] Lee P, Wang CC, Adamis AP. Ocular neovascularization: an epidemiologic review. Surv

[18] Mochimaru H, Usui T, Yaguchi T, Nagahama Y, Hasegawa G, Usui Y, Shimmura S, Tsubota K, Amano S, Kawakami Y, Ishida S. Suppression of alkali burn‐induced cor‐ neal neovascularization by dendritic cell vaccination targeting VEGF receptor 2. Invest

[19] Applegate LA, Ley RD. DNA damage is involved in the induction of opacifica‐ tion and neovascularization of the cornea by ultraviolet radiation. Exp Eye Res

[21] Javadi MA, Jafarinasab MR, Feizi S, Karimian F, Negahban K. Management of mustard gas‐induced limbal stem cell deficiency and keratitis. Ophthalmology

[22] Chang JH, Garg NK, Lunde E, Han KY, Jain S, Azar DT. Corneal neovascularization: an

[23] Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor

[20] Cogan DG. Corneal vascularization. Invest Ophthalmol Vis Sci 1962;1:253–261.

anti‐VEGF therapy review. Surv Ophthalmol 2012;57(5):415–429.

(VEGF) and its receptors. FASEB J 1999;13(1):9–22.

and lymphangiogenesis in corneal pathology. Cornea 2012;31(1):74–80.

72 Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

Cornea 1990;9(2):144–1451.

cornea tissues. J Infect Dis 2009;200(1):11–19.

2003;136(5):957–958.

2009;154(2):219–226.

2000;44(5):415–425.

2010;77(5):409–420.

1991;52(4):493–497.

2011;118(7):1272–1281.

Ophthalmol 1998;43(3):245–269.

Ophthalmol Vis Sci 2008;49(5):2172–2177.


[51] Hos D1, Bock F, Dietrich T, Onderka J, Kruse FE, Thierauch KH, Cursiefen C. Inflammatory corneal (lymph) angiogenesis is blocked by VEGFR‐tyrosine kinase inhib‐ itor ZK 261991, resulting in improved graft survival after corneal transplantation. Invest Ophthalmol Vis Sci 2008;49(5):1836–1842.

[36] Wu PC, Liu CC, Chen CH, Kou HK, Shen SC, Lu CY, Chou WY, Sung MT, Yang LC. Inhibition of experimental angiogenesis of cornea by somatostatin. Graefes Arch Clin

[37] You IC, Kang IS, Lee SH, Yoon KC. Therapeutic effect of subconjunctival injection of bevacizumab in the treatment of corneal neovascularization. Acta Ophthalmol

[38] Jhanji V, Liu H, Law K, Lee VY, Huang SF, Pang CP, Yam GH. Isoliquiritigenin from licorice root suppressed neovascularisation in experimental ocular angiogenesis models.

[39] Kirwan RP, Zheng Y, Tey A, Anijeet D, Sueke H, Kaye SB. Quantifying changes in cor‐ neal neovascularization using fluorescein and indocyanine green angiography. Am J

[40] Kwan AS, Barry C, McAllister IL, Constable I. Fluorescein angiography and adverse drug reactions revisited: the Lions Eye experience. Clin Experiment Ophthalmol 2006;34(1):33–38.

[41] Hope‐Ross M, Yannuzzi LA, Gragoudas ES, Guyer DR, Slakter JS, Sorenson JA, Krupsky S, Orlock DA, Puliafito CA. Adverse reactions due to indocyanine green. Ophthalmology

[42] Steger B, Romano V, Kaye SB. Corneal indocyanine green angiography to guide medical and surgical management of corneal neovascularization. Cornea 2016;35(1):41–45. [43] Romano V, Spiteri N, Kaye SB. Angiographic‐guided treatment of corneal neovascular‐

[44] Al‐Torbak A, Al‐Amri A, Wagoner MD. Deep corneal neovascularization after implan‐ tation with intrastromal corneal ring segments. Am J Ophthalmol 2005;140(5):926–927.

[45] Brooks BJ, Ambati BK, Marcus DM, Ratanasit A. Photodynamic therapy for corneal neo‐

[46] Baer JC, Foster CS. Corneal laser photocoagulation for treatment of neovascularization.

[47] L'sEsperance FA Jr. Clinical photocoagulation with organic dye laser. A preliminary

[48] Faraj LA, Elalfy MS, Said DG, Dua HS. Fine needle diathermy occlusion of corneal ves‐

[49] Liang L, Li W, Ling S, Sheha H, Qiu W, Li C, Liu Z. Amniotic membrane extraction solu‐

[50] Oliveira HB, Sakimoto T, Javier JA, Azar DT, Wiegand SJ, Jain S, Chang JH. VEGF Trap(R1R2) suppresses experimental corneal angiogenesis. Eur J Ophthalmol

vascularisation and lipid degeneration. Br J Ophthalmol 2004;88(6):840.

Efficacy of 577 nm yellow dye laser. Ophthalmology 1992;99(2):173–179.

tion for ocular chemical burns. Clin Exp Ophthalmol 2009;37(9):855–863.

communication. Arch Ophthalmol 1985;103(9):1312–1316.

sels. Br J Ophthalmol 2014;98(9):1287–1290.

Exp Ophthalmol 2003;241(1):63–69.

74 Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

Br J Ophthalmol 2011;95(9):1309–1315.

ization. JAMA Ophthalmol 2015;133(3):e143544.

Ophthalmol 2012;154(5):850–858.

2009;87(6):653–658.

1994;101(3):529–533.

2010;20(1):48–54.


## **Angiogenesis-Related Factors in Early Pregnancy Loss Angiogenesis-Related Factors in Early Pregnancy Loss**

Marina M. Ziganshina, Lyubov V. Krechetova, Lyudmila V. Vanko, Zulfiya S. Khodzhaeva, Ekaterina L. Yarotskaya and Gennady T. Sukhikh Marina M. Ziganshina, Lyubov V. Krechetova, Lyudmila V. Vanko, Zulfiya S. Khodzhaeva, Ekaterina L. Yarotskaya and Gennady T. Sukhikh

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/66410

#### **Abstract**

[63] Chen WL, Chen YM, Chu HS, Lin CT, Chow LP, Chen CT, Hu FR. Mechanisms control‐ ling the effects of bevacizumab (avastin) on the inhibition of early but not late formed cor‐ neal neovascularization. PLoS One 2014;9(4):e94205. doi:10.1371/journal.pone.0094205.

76 Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

[64] Kim TI, Chung JL, Hong JP, Min K, Seo KY, Kim EK. Bevacizumab application delays epithelial healing in rabbit cornea. Invest Ophthalmol Vis Sci 2009;50(10):4653–4659. [65] Koenig Y, Bock F, Horn F, Kruse F, Straub K, Cursiefen C. Short‐ and long‐term safety profile and efficacy of topical bevacizumab (Avastin) eye drops against corneal neovas‐

[66] Stevenson W, Cheng SF, Dastjerdi MH, Ferrari G, Dana R. Corneal neovasculariza‐ tion and the utility of topical VEGF inhibition: ranibizumab (Lucentis) vs bevacizumab

[67] Liarakos VS, Papaconstantinou D, Vergados I, Douvali M, Theodossiadis PG. The effect of subconjunctival ranibizumab on corneal and anterior segment neovascularization:

[68] Duh EJ, Yang HS, Suzuma I, Miyagi M, Youngman E, Mori K, Katai M, Yan L, Suzuma K, West K, Davarya S, Tong P, Gehlbach P, Pearlman J, Crabb JW, Aiello LP, Campochiaro PA, Zack DJ. Pigment epithelium‐derived factor suppresses ischemia‐induced retinal neovascularization and VEGF‐induced migration and growth. Invest Ophthalmol Vis

[69] Mori K, Gehlbach P, Ando A, McVey D, Wei L, Campochiaro PA. Regression of ocular neovascularization in response to increased expression of pigment epithelium‐derived

[70] Shao C, Sima J, Zhang SX, Jin J, Reinach P, Wang Z, Ma JX. Suppression of corneal neo‐ vascularization by PEDF release from human amniotic membranes. Invest Ophthalmol

[71] Jin J, Ma JX, Guan M, Yao K. Inhibition of chemical cautery‐induced corneal neo‐ vascularization by topical pigment epithelium‐derived factor eyedrops. Cornea

[72] Onder HI, Erdurmus M, Bucak YY, Simavli H, Oktay M, Kukner AS. Inhibitory effects of regorafenib, a multiple tyrosine kinase inhibitor, on corneal neovascularization. Int J

[73] Pérez‐Santonja JJ1, Campos‐Mollo E, Lledó‐Riquelme M, Javaloy J, Alió JL. Inhibition of corneal neovascularization by topical bevacizumab (Anti‐VEGF) and sunitinib (Anti‐ VEGF and Anti‐PDGF) in an animal model. Am J Ophthalmol 2010;150(4):519–528. [74] Kaya MK, Demir T, Bulut H, Akpolat N, Turgut B. Effects of lapatinib and trastuzumab on vascular endothelial growth factor in experimental corneal neovascularization. Clin

cularization. Graefes Arch Clin Exp Ophthalmol 2009;247(10):1375–1382.

study on an animal model. Eur J Ophthalmol 2014;24(3):299–308.

factor. Invest Ophthalmol Vis Sci 2002;43(7):2428–2434.

(Avastin). Ocul Surf 2012;10(2):67–83.

Sci 2002;43(3):821–829.

Vis Sci 2004;45(6):1758–1762.

Ophthalmol 2014;7(2):220–225.

Exp Ophthalmol 2015;43(5):449–457.

2010;29(9):1055–1061.

The habitual loss of early pregnancy is one of the major problems of obstetrics now‐ adays, provided that the cause of more than 50% of all early pregnancy losses is unknown. Adequate angiogenesis is one of the main indicators of proper formation of placental system, making the basis of fetal life support. The objective description of angiogenesis in physiological development of pregnancy and in pathological condi‐ tions is complicated by the difficulties in obtaining and characterizing placental tis‐ sue in early pregnancy. Thus, angiogenesis‐related factors are promising indicators to characterize angiogenesis in pregnancy. This chapter draws attention to alteration in angiogenesis‐related factors in peripheral blood of patients with habitual early preg‐ nancy losses. Investigation of factors (vascular endothelial growth factor (VEGF), sFlt‐1, sKDR, metalloproteinase (MMP)‐2, MMP‐9, tissue inhibitor (TIMP)‐1, TIMP‐2 and pla‐ cental growth factor (PLGF)), which specifically and nonspecifically regulate angio‐ genesis in pregnancy, was performed in the most significant terms for placentogenesis: 6 weeks, 7–8 weeks and 11–14 weeks of pregnancy. It was found that in a missed abor‐ tion there was a significant imbalance of angiogenesis‐related factors compared with normal pregnancy. These results reflect a disturbance of angiogenesis in a missed abor‐ tion and point to the importance of the studied factors in the pathogenesis of early pregnancy losses.

**Keywords:** Angiogenesis, angiogenic factors, pregnancy, angiogenesis inhibitors, matrix metalloproteinases, pro‐ and antiangiogenic factors ratio, VEGF/VEGF‐R1, VEGF/VEGF‐R2, MMP‐9/TIMP‐1

and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
