Vascular endothelial growth factor from retinal pigment epithelium is essential in choriocapillaris and axial length maintenance

Abstract

Myopia, which prevalence is rapidly increasing, causes visual impairment; however, the onset mechanism of pathological axial length (AL) elongation remains unclear. A highly vascularized choroid between the retinal pigment epithelium (RPE) and sclera not only maintains physiological activities, but also contributes to ocular development and growth regulation. Vascular endothelial growth factor (VEGF) secreted from the RPE to the choroid is essential for retinal function and maintenance of the choriocapillaris. Herein, we demonstrated that the loss of VEGF secreted from the RPE caused abnormal choriocapillaris development and AL elongation, with features similar to those of the lens-induced myopia (LIM) mouse model, whereas VEGF overexpression by knocking-out von Hippel–Lindau (VHL) specific to the RPE expands the choriocapillaris and shortens the AL. Additionally, LDL Receptor Related Protein 2 (LRP2) deletion in the RPE downregulated VEGF expression and leads to pathological AL elongation. Furthermore, high myopia patients without choriocapillaris demonstrated longer ALs than did those with preserved choriocapillaris. These results suggest that physiological secretion of VEGF from the RPE is required for proper AL development by maintaining the choriocapillaris. The pinpoint application of VEGF to the choriocapillaris may become a potential intervention for the prevention and treatment of axial myopia progression.

Myopia Is Suppressed by Digested Lactoferrin or Holo-Lactoferrin Administration

“…Vascular endothelial growth factor is a dimeric glycoprotein that stimulates neovascularization [ 30 ]. Studies have shown that low levels of vascular endothelial growth factor (VEGF) A expression are associated with choroidal thinning, decreased choroidal vessels, and AL elongation [ 31 , 32 ]. Figure 2 B shows that in the PBS control group, the choroid of −30 D LIM eyes had significantly higher IL-8 ( p < 0.01) mRNA expression than that of 0 D eyes, whereas the expression levels were low in the group administered native-LF and its hydrolysates.…”

Molecular and Cellular Regulations in the Development of the Choroidal Circulation System

“…The doxycycline-inducible and RPE-specific deletion of Vegfa in Best1-rtTA;TRE-Cre;Vegfa flox/flox mice at the middle gestational stage from E10 to E15, but not at later than E16, induces a lower density in both the choriocapillaris and larger choroidal vessels after birth [ 42 ]. Tyrp1-Cre tg/0 ;Vegfa flox/flox mice and Best1-Cre;Vegfa flox/flox mice ( Vegfa RPE KO mice), who lack the Vegfa gene specifically in RPE cells, show hypoplasia of the choriocapillaris [ 43 , 44 ]. Vegfa RPE KO mice also exhibit the phenotypes of myopia, such as the elongation of axial length and decreased refraction at 4 weeks after birth [ 44 ].…”

“…Tyrp1-Cre tg/0 ;Vegfa flox/flox mice and Best1-Cre;Vegfa flox/flox mice ( Vegfa RPE KO mice), who lack the Vegfa gene specifically in RPE cells, show hypoplasia of the choriocapillaris [ 43 , 44 ]. Vegfa RPE KO mice also exhibit the phenotypes of myopia, such as the elongation of axial length and decreased refraction at 4 weeks after birth [ 44 ]. Contrary to Vegfa RPE KO mice, vasodilatation is observed in Best1-Cre;Vhl flox/flox mice, showing increased expression of Vegfa in RPE cells.…”

“…Lrp2 -mutant (Lrp2 267/− ) mice also exhibit ocular anomalies, including a thin retina, hyperplasia of the non-pigmented epithelium of the ciliary body, and enlarged and exophthalmic eyes with great elongation of axial length, which is a sign of severe myopia [ 53 ]. Interestingly, we found that the Best1-Cre;Lrp2 flox/flox ( Lrp2 RPE KO) mice, who lack the Lrp2 gene specifically in the RPE, reproduce most of the morphological changes in the eyes from the Lrp2 267/− mice, i.e., thin retina, enlarged eyes, and elongation of axial length [ 44 ]. In addition to such changes, the thinner choroid and the thinner sclera are reported in Lrp2 RPE KO mice.…”

“…The thinning of the choroid in Lrp2 RPE KO mice is accompanied by the decreased expression of Vegfa in RPE cells and is due to severe hypoplasia of the choriocapillaris as well as Vegfa RPE KO mice. In neural retina-specific Lrp2 deletion mice ( Chx10-Cre;Lrp2 flox/flox mice), enlarged eyes, axial length elongation, and hypoplasia of the choriocapillaris are not observed [ 44 ]. Therefore, the LRP2-VEGFA axis in RPE cells largely contributes to the development of the choriocapillaris.…”