HTRA1 Regulates Subclinical Inflammation and Activates Proangiogenic Response in the Retina and Choroid

• Published in: International journal of molecular sciences Vol. 23; no. 18; p. 10206
• Main Authors: Ahamed, Waseem, Yu, Richard Ming Chuan, Pan, Yang, Iwata, Takeshi, Barathi, Veluchamy Amutha, Wey, Yeo Sia, Tun, Sai Bo Bo, Qiu, Beiying, Tan, Alison, Wang, Xiaomeng, Cheung, Chui Ming Gemmy, Wong, Tien Yin, Yanagi, Yasuo
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 06.09.2022; MDPI
• Subjects: age-related macular degeneration; Angiogenesis; Animals; Cell activation; Choroid - blood supply; Choroidal Neovascularization - genetics; Choroidal Neovascularization - pathology; Explants; High temperature; High-Temperature Requirement A Serine Peptidase 1 - genetics; HtrA1 mice; In vivo methods and tests; Inflammation; Inflammation - genetics; Inflammation - pathology; Leakage; Macrophages; Macular degeneration; Macular Degeneration - genetics; Macular Degeneration - pathology; Medical imaging; Mice; Mice, Transgenic; Monocytes; Peripheral blood; Polymorphism; polypoidal choroidal neovascularization; proangiogenic response; Retina; Retina - pathology; RNA-sequencing; Rodents; subclinical inflammation; Temperature requirements; Tomography; Transgenic mice; Trinucleotide repeats; Vascularization; HtrA1 mice; RNA-sequencing; immune system process GO-terms; polypoidal choroidal neovascularization; KEGG & Reactome pathways; age-related macular degeneration; proangiogenic response; subclinical inflammation
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms231810206

High-temperature requirement A1 (HtrA1) has been identified as a disease-susceptibility gene for age-related macular degeneration (AMD) including polypoidal choroidal neovasculopathy (PCV). We characterized the underlying phenotypic changes of transgenic (Tg) mice expressing ubiquitous CAG promoter (CAG-HtrA1 Tg). In vivo imaging modalities and histopathology were performed to investigate the possible neovascularization, drusen formation, and infiltration of macrophages. Subretinal white material deposition and scattered white-yellowish retinal foci were detected on CFP [(Tg—33% (20/60) and wild-type (WT)—7% (1/15), p < 0.05]. In 40% (4/10) of the CAG-HtrA1 Tg retina, ICGA showed punctate hyperfluorescent spots. There was no leakage on FFA and OCTA failed to confirm vascular flow signals from the subretinal materials. Increased macrophages and RPE cell migrations were noted from histopathological sections. Monocyte subpopulations were increased in peripheral blood in the CAG-HtrA1 Tg mice (p < 0.05). Laser induced CNV in the CAG-HtrA1 Tg mice and showed increased leakage from CNV compared to WT mice (p < 0.05). Finally, choroidal explants of the old CAG-HtrA1 Tg mice demonstrated an increased area of sprouting (p < 0.05). Signs of subclinical inflammation was observed in CAG-HtrA1 Tg mice. Such subclinical inflammation may have resulted in increased RPE cell activation and angiogenic potential.