title: Increased expression of multifunctional serine protease, HTRA1, in retinal pigment epithelium induces polypoidal choroidal vasculopathy in mice.
abstract: Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly. Wet AMD includes typical choroidal neovascularization (CNV) and polypoidal choroidal vasculopathy (PCV). The etiology and pathogenesis of CNV and PCV are not well understood. Genome-wide association studies have linked a multifunctional serine protease, HTRA1, to AMD. However, the precise role of HTRA1 in AMD remains elusive. By transgenically expressing human HTRA1 in mouse retinal pigment epithelium, we showed that increased HTRA1 induced cardinal features of PCV, including branching networks of choroidal vessels, polypoidal lesions, severe degeneration of the elastic laminae, and tunica media of choroidal vessels. In addition, HTRA1 mice displayed retinal pigment epithelium atrophy and photoreceptor degeneration. Senescent HTRA1 mice developed occult CNV, which likely resulted from the degradation of the elastic lamina of Bruch's membrane and up-regulation of VEGF. Our results indicate that increased HTRA1 is sufficient to cause PCV and is a significant risk factor for CNV.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Jones
authors.forename: Sandeep
authors.initials: S
authors.lastname: Kumar
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.forename: Zongzhong
authors.initials: Z
authors.lastname: Tong
authors.forename: Jia-Hui
authors.initials: JH
authors.lastname: Yang
authors.forename: Carl
authors.initials: C
authors.lastname: Watt
authors.forename: James
authors.initials: J
authors.lastname: Anderson
authors.lastname: Amrita
authors.forename: Heather
authors.initials: H
authors.lastname: Fillerup
authors.forename: Manabu
authors.initials: M
authors.lastname: McCloskey
authors.forename: Ling
authors.initials: L
authors.lastname: Luo
authors.forename: Zhenglin
authors.initials: Z
authors.lastname: Yang
authors.forename: Balamurali
authors.initials: B
authors.lastname: Ambati
authors.forename: Robert
authors.initials: R
authors.lastname: Marc
authors.forename: Chio
authors.initials: C
authors.lastname: Oka
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.forename: Yingbin
authors.initials: Y
authors.lastname: Fu
mesh_terms: D000818:Animals; D020256:Choroidal Neovascularization / Q000209:etiology; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D008268:Macular Degeneration / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009389:Neovascularization, Pathologic; D010196:Pancreatic Elastase / Q000378:metabolism; D011506:Proteins / Q000502:physiology; D055213:Retinal Pigment Epithelium / Q000201:enzymology*; D012697:Serine Endopeptidases / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
chemical_list: C514392:ARMS2 protein, human; D011506:Proteins; D042461:Vascular Endothelial Growth Factor A; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; C492073:HtrA1 protein, mouse; D012697:Serine Endopeptidases; D010196:Pancreatic Elastase