Department of Ophthalmology and Visual Sciences, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
Proc Natl Acad Sci U S A. 2011 Aug 30;108(35):14578-83. doi: 10.1073/pnas.1102853108. Epub 2011 Aug 15.
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.
年龄相关性黄斑变性（AMD）是老年人不可逆性失明的主要原因。湿性 AMD 包括典型脉络膜新生血管（CNV）和息肉状脉络膜血管病变（PCV）。CNV 和 PCV 的病因和发病机制尚不清楚。全基因组关联研究将一种多功能丝氨酸蛋白酶 HTRA1 与 AMD 联系起来。然而，HTRA1 在 AMD 中的确切作用仍不清楚。通过在小鼠视网膜色素上皮中转基因表达人 HTRA1，我们发现 HTRA1 的增加诱导了 PCV 的主要特征，包括脉络膜血管的分支网络、息肉样病变、脉络膜血管弹性层和中膜的严重退化。此外，HTRA1 小鼠表现出视网膜色素上皮萎缩和光感受器变性。衰老的 HTRA1 小鼠发生隐匿性 CNV，这可能是由于 Bruch 膜的弹性层降解和 VEGF 的上调所致。我们的结果表明，HTRA1 的增加足以引起 PCV，并且是 CNV 的重要危险因素。
