Angiogenesis refers to formation of a new blood vessel branch by endothelial cell proliferation and migration and remodeling from a pre-existing blood vessel of a tissue. In recent years, the mechanism of angiogenesis has drastically been revealed by cell biological approaches. Angiogenesis is started by induced expression of VEGF (vascular endothelial growth factor) mRNA which occurs by activation of a transcription factor HIF (hypoxia-inducible factor) responding to ischemia-based hypoxia. The produced VEGF binds to a VEGF receptor (VEGFR) localized in a vascular endothelial cell, and activates an intracellular signaling pathway. This results in decomposed extracellular basement membrane, followed stepwise by vascular endothelial cell migration/proliferation, lumen formation of vascular endothelial cell, basement membrane formation, and pericyte enclosure, finally resulting in angiogenesis.
According to Murohara T. et al., “Nitric Oxide and Angiogenesis in Cardiovascular Disease”, Antioxidants & Redox Signaling, Vol. 4, pp. 825-831 (2002) (NPL 1), a pathway starting from phosphatidylinositol-3-kinase (PI3K) is clarified as an intracellular signaling pathway involved in angiogenesis. In the PI3K pathway, activation of endothelial NO synthase (eNOS), and thereby increasing NO production, are confirmed, and according to Noiri E. et al., “Podokinesis in endothelial cell migration: role of nitric oxide”, The American Physiological Society, Vol. 274, pp. 236-244 (1998) (NPL 2), Ziche M. et al., “Nitric Oxide Promotes Proliferation and Plasminogen Activator Production by Coronary Venular Endothelium Through Endogenous bFGF”, Circulation Research, Vol. 80, pp. 845-852 (1997) (NPL 3), and Dimmeler S. et al., “Upregulation of Superoxide Dismutase and Nitric Oxide Synthase Mediates the Apoptosis-Suppressive Effects of Shear Stress on Endothelial Cells”, Arterioscler. Thromb. Vasc. Biol., Vol. 19, pp. 656-664 (1999) (NPL 4), currently it is believed that endogenous nitrogen monoxide promotes angiogenesis by its vascular endothelial cell proliferation and migration promoting effect and an apoptosis-suppressive effect.
In clinical medicine, it is known that angiogenesis has a large influence on wound-healing and the progress of many diseases. Diseases known as involving angiogenesis include retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, neovascular glaucoma and other ophthalmologic diseases, rheumatoid arthritis and other inflammatory diseases, solid tumors and other malignant neoplasms, and the like, and these diseases present pathologic neovascularization lacking a regulation mechanism. For ophthalmologic diseases, pathologic neovascularization has been treated strategically consistently by its suppression and inhibition, generally categorized into surgical treatment and medication, as disclosed in Japanese Patent Laying-Open No. 2002-284685 (PTL 1) and Japanese Patent Laying-Open No. 2008-110950 (PTL 2).
Although a laser photocoagulation is generally used as a representative surgical treatment, this treatment is compensatory tissue destruction applied reluctantly in a pathologically advanced stage, which may cause reducing peripheral vision loss and night vision difficulties, and a change of color vision.
In medication, inhibitors which block different stages of an intracellular signaling pathway in angiogenesis have been studied and developed by molecular-biologically elucidating mechanism of angiogenesis. A VEGF antibody (Bevacizumab), and a nucleic acid (Pegaptanib sodium), which specifically binds to VEGF as described in Japanese Patent Laying-Open No. 2008-280356 (PTL 3), have been invented and developed as VEGF inhibitors. While these inhibitors are effective in inhibiting pathologic neovascularization of retinopathy and in diabetic macular edema, it has been reported that the anti-VEGF antibody inhibits physiological neovascularization and causes systemic wound-healing retardation, cerebral hemorrhage, cerebrovascular accidents, myocardial infarction, angina pectoris, and other serious side effects.
According to Eyal B. et al., “T2-TrpRS Inhibits Preretinal Neovascularization and Enhances Physiological Vascular Regrowth in OIR as Assessed by a New Method of Quantification”, Investigative Ophthalmology & Visual Science, Vol. 47, pp. 2125-2134 (2006) (NPL 5), inhibition of pathologic neovascularization is attempted by suppressing production of endogenous nitrogen monoxide using a nitrogen monoxide synthase inhibitor. It is predicted that aggravation of diabetes as an underlying disease for retinopathy, elevation of blood pressure, myocardial infarction, angina pectoris and expression of other various systemic side effects are caused by strongly inhibiting molecules, such as nitrogen monoxide, that play a physiologically important role.
Furthermore, because VEGF inhibitor and other similar ophthalmovascular therapeutic agents are administered to a patient through intravitreous injection to alleviate a systemic side effect, this treatment imposes a large burden on the patients, and the intravitreous injection not only injures the patients' ocular tissues but will also constantly expose their lenses and retinal tissues to a risk of bacterial infection.