Roles of lipocalin-type and hematopoietic prostaglandin D synthases in mouse retinal angiogenesis

Daiki Horikami; Erika Sekihachi; Keisuke Omori; Yui Kobayashi; Koji Kobayashi; Nanae Nagata; Kaori Kurata; Akiyoshi Uemura; Takahisa Murata

doi:10.1016/j.jlr.2023.100439

Roles of lipocalin-type and hematopoietic prostaglandin D synthases in mouse retinal angiogenesis

J Lipid Res. 2023 Oct;64(10):100439. doi: 10.1016/j.jlr.2023.100439. Epub 2023 Sep 4.

Authors

Daiki Horikami¹, Erika Sekihachi¹, Keisuke Omori¹, Yui Kobayashi¹, Koji Kobayashi¹, Nanae Nagata¹, Kaori Kurata², Akiyoshi Uemura², Takahisa Murata³

Affiliations

¹ Department of Animal Radiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
² Department of Retinal Vascular Biology, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya, Japan.
³ Department of Animal Radiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. Electronic address: amurata@mail.ecc.u-tokyo.ac.jp.

Abstract

Normal angiogenesis is essential for retinal development and maintenance of visual function in the eye, and its abnormality can cause retinopathy and other eye diseases. Prostaglandin D₂ is an anti-angiogenic lipid mediator produced by lipocalin-type PGD synthase (L-PGDS) or hematopoietic PGD synthase (H-PGDS). However, the exact role of these PGD synthases remains unclear. Therefore, we compared the roles of these synthases in murine retinal angiogenesis under physiological and pathological conditions. On postnatal day (P) 8, the WT murine retina was covered with an elongated vessel. L-PGDS deficiency, but not H-PGDS, reduced the physiological vessel elongation with sprouts increase. L-PGDS expression was observed in endothelial cells and neural cells. In vitro, L-PGDS inhibition increased the hypoxia-induced vascular endothelial growth factor expression in isolated endothelial cells, inhibited by a prostaglandin D₂ metabolite, 15-deoxy-Δ^12,14 -PGJ₂ (15d-PGJ₂) treatment. Pericyte depletion, using antiplatelet-derived growth factor receptor-β antibody, caused retinal hemorrhage with vessel elongation impairment and macrophage infiltration in the WT P8 retina. H-PGDS deficiency promoted hemorrhage but inhibited the impairment of vessel elongation, while L-PGDS did not. In the pericyte-depleted WT retina, H-PGDS was expressed in the infiltrated macrophages. Deficiency of the D prostanoid receptor also inhibited the vessel elongation impairment. These results suggest the endogenous role of L-PGDS signaling in physiological angiogenesis and that of H-PGDS/D prostanoid 1 signaling in pathological angiogenesis.

Keywords: Prostaglandin D(2); endothelial cells; hematopoietic PGD synthase; lipocalin-type PGD synthase; neovascularization; pathologic; physiologic.