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

Yan Zhang; Heonuk Jeong; Kiwako Mori; Shin-Ichi Ikeda; Chiho Shoda; Yukihiro Miwa; Ayaka Nakai; Junhan Chen; Ziyan Ma; Xiaoyan Jiang; Hidemasa Torii; Yoshiaki Kubota; Kazuno Negishi; Toshihide Kurihara; Kazuo Tsubota

doi:10.1093/pnasnexus/pgac166

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

PNAS Nexus. 2022 Aug 24;1(4):pgac166. doi: 10.1093/pnasnexus/pgac166. eCollection 2022 Sep.

Authors

Yan Zhang^{1

2}, Heonuk Jeong^{1

2}, Kiwako Mori^{1

2}, Shin-Ichi Ikeda^{1

2}, Chiho Shoda^{1

2

3}, Yukihiro Miwa^{1

2

4}, Ayaka Nakai^{1

2

3}, Junhan Chen^{1

2}, Ziyan Ma^{1

2}, Xiaoyan Jiang^{1

2}, Hidemasa Torii^{1

2}, Yoshiaki Kubota⁵, Kazuno Negishi², Toshihide Kurihara^{1

2}, Kazuo Tsubota^{2

6}

Affiliations

¹ Laboratory of Photobiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
² Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
³ Department of Ophthalmology, Nihon University School of Medicine, 30-1 Oyaguchikamicho, Itabashi City, Tokyo 173-8610, Japan.
⁴ Aichi Animal Eye Clinic, 3 Chome-17-3 Honjitori, Minami Ward, Nagoya, Aichi 457-0074, Japan.
⁵ Department of Anatomy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
⁶ Tsubota Laboratory Inc., 34 Shinanomachi, 304 Toshin Shinanomachi Ekimae Building, Shinjuku-ku, Tokyo 160-0016, Japan.

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.

Keywords: VEGF; axial length; choriocapillaris; myopia.