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Page 184 Ma et al. J Transl Genet Genom 2022;6:179-203 https://dx.doi.org/10.20517/jtgg.2021.48

sclera. Meanwhile, the thin choroid in high myopia patients is not competent to buffer the mechanical stress
caused by myopia development. In patients with the thin choroid, the force would concentrate in the area of
scleral perforating vessels and cause the disruption of RPE and Bruch’s membrane. In this way, the mCNV
[45]
grows through the fissure into the subretinal space and tries to fix the mechanical break .

Loss of choroidal vessels causes a choroidal circulatory disturbance, induces hypoxia in the RPE and glial
[47]
cells, and triggers upregulation of vascular endothelial growth factor (VEGF) expression . VEGF is a
family of proteins including VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placenta growth factor . VEGF-A
[48]
is the key regulator for angiogenesis . The receptors of VEGF are VEGFR-1, VEGFR-2, and VEGFR-3. The
[48]
former two are expressed predominantly on vascular endothelial cells, while VEGFR-3 is expressed on
[49]
lymphatic endothelial cells . VEGF interacts with VEGFR-1 and VEGFR-2 to initiate an intracellular
cascade and induce proliferation and migration of vascular endothelial cells and inhibit apoptosis . In
[50]
addition to hypoxia-induced expression of VEGF, the mechanical stress posed on RPE induces expression
[51]
and secretion of VEGF .

VEGF, as a common contributor in different types of CNV, can be detected in aqueous humor and vitreous
body. The physiologic expression of VEGF levels is lower in the eyes of highly myopic patients than those of
non-myopia patients . The VEGF level elevates in myopic patients with CNV compared to those without
[47]
CNV . When compared with other types of CNV, the VEGF level in the aqueous humor of mCNV
[47]
patients was lower [52,53] . Several possible explanations for this have been proposed. Firstly, dysfunction of
RPE cells causes less expression of VEGF. VEGF, which is expressed by differentiated RPE cells, is essential
in the maintenance of choriocapillaris [54,55] . In high myopia, the deteriorated function of RPE cells causes a
reduction of VEGF production and corresponding atrophy of choriocapillaris . Secondly, the large
[56]
vitreous cavity of myopic eyes could dilute VEGF concentration. In highly myopic patients, whether with
CNV or not, the VEGF concentration is negatively correlated with AL [47,57] . Researchers have argued that the
limited amount of VEGF localized to mCNV is not sufficient to distribute into the anterior chamber.
Thirdly, the decrease of VEGF production is due to retinal thinning in myopic eyes. Sawada et al.
[52]
proposed that retinal thinning in myopia patients causes a relative increase in choroidal perfusion.
Consequently, retinal hypoxia would be improved, and VEGF production would decrease, correspondingly.

In addition to hypoxia-induced expression of VEGF, the aqueous cytokines indicate that inflammation has
a role in the development of mCNV . In the study by Yamamoto et al. , the levels of interleukin-8 (IL-8)
[58]
[58]
and VEGF were significantly higher in eyes with mCNV. IL-8 is a proangiogenic and inflammatory
[59]
chemokine that can upregulate VEGF expression in ischemic circumstances . Beyond that, the interleukin-
10 (IL-10) and monocyte chemoattractant protein-1 (MCP-1) levels were higher in myopic eyes than in
normal eyes in this study. Furthermore, IL-8 and MCP-1 were related to the severity of myopic
maculopathy. MCP-1 is a chemokine that regulates monocyte chemotaxis and lymphocyte differentiation in
[60]
inflammatory diseases . Thus, it is suggested that inflammation is involved in the progression of myopic
maculopathy and the etiology of mCNV.

Genetic factors also play a part in the development of mCNV. Leveziel et al. compared mCNV cases with
[61]
high myopia cases and evaluated 15 age-related macular degeneration genetic variants which could also be
involved in mCNV development. They found that the rs10033900 single nucleotide polymorphism (SNP)
located in CFI gene was significantly associated with mCNV in Caucasians. CFI encodes complement factor
I (CFI), which is a complement regulatory protein in the classical, alternative, and mannose-binding lectin
pathways of the complement system . CFI is expressed by hepatocytes, macrophages, lymphocytes,
[62]
endothelial cells, and fibroblasts . CFI works as a protease to prevent positive amplification of complement
[63]