Increased cell stiffness contributes to complement-mediated injury of choroidal endothelial cells in a monkey model of early age-related macular degeneration.
Increased cell stiffness contributes to complement-mediated injury of choroidal endothelial cells in a monkey model of early age-related macular degeneration.
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早期年龄相关性黄斑变性猴模型中细胞硬度增加导致补体介导的脉络膜内皮细胞损伤
DOI：
10.1002/path.5892
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发表时间：
2022-07
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影响因子：
--
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中科院分区：
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视网膜相关性黄斑变性（AMD）是老年人失明的主要原因。然而，对于约85%的具有以视网膜色素上皮（RPE）和下面的脉络膜脉管系统的变性为标志的干性形式的AMD患者，没有治疗存在。由于脉络膜血管对于RPE的发展和维持至关重要，因此了解它们如何退化可能会导致干性AMD的有效治疗。脉络膜血管损失的一个可能的致病因素是补体途径的溶细胞膜攻击复合物（MAC），其在患有早期干性AMD的人的脉络膜血管上丰富。为了研究这种可能性，我们研究了补体激活对脉络膜内皮细胞（EC）的影响，从恒河猴模型分离的早期AMD，我们报告，表现出MAC沉积和脉络膜毛细血管内皮细胞损失类似于人类早期AMD。用具有补体活性的正常人血清治疗AMD眼的脉络膜EC引起广泛的肌动蛋白细胞骨架损伤，这在年轻正常猴眼的脉络膜EC中显著不太明显。我们进一步表明，从AMD的眼睛EC是显着僵硬比年轻的同行，并表现出周边肌动蛋白组织，这是不同的纵向应力纤维在年轻的EC。最后，发现补体敏感性和机械结构特性的这些差异受小GTP酶Rac和Rho的差异活性调节，因为AMD细胞中的Rac抑制导致硬度和补体敏感性同时降低，而年轻细胞中的Rho抑制加剧了补体损伤。因此，通过鉴定细胞硬度和细胞骨架调节因子Rac和Rho作为补体易感性的重要决定因素，目前的研究结果提供了对早期AMD脉络膜血管损失的新的机制见解，这需要进一步研究以评估翻译潜力。
Age-related macular degeneration (AMD) is the leading cause of blindness in the aging population. Yet, no therapies exist for approximately 85% of all AMD patients who have the dry form that is marked by degeneration of the retinal pigmented epithelium (RPE) and underlying choroidal vasculature. As the choroidal vessels are crucial for RPE development and maintenance, understanding how they degenerate may lead to effective therapies for dry AMD. One likely causative factor for choroidal vascular loss is the cytolytic membrane attack complex (MAC) of the complement pathway that is abundant on choroidal vessels of humans with early dry AMD. To examine this possibility, we studied the effect of complement activation on choroidal endothelial cells (ECs) isolated from a rhesus monkey model of early AMD that, we report, exhibits MAC deposition and choriocapillaris endothelial loss similar to that seen in human early AMD. Treatment of choroidal ECs from AMD eyes with complement-competent normal human serum caused extensive actin cytoskeletal injury that was significantly less pronounced in choroidal ECs from young normal monkey eyes. We further show that ECs from AMD eyes are significantly stiffer than their younger counterparts and exhibit peripheral actin organization that is distinct from the longitudinal stress fibers in young ECs. Finally, these differences in complement susceptibility and mechanostructural properties were found to be regulated by the differential activity of the small GTPases Rac and Rho, because Rac inhibition in AMD cells led to simultaneous reduction in stiffness and complement susceptibility while Rho inhibition in young cells exacerbated complement injury. Thus, by identifying cell stiffness and cytoskeletal regulators Rac and Rho as important determinants of complement susceptibility, the current findings offer a new mechanistic insight into choroidal vascular loss in early AMD that warrants further investigation for assessment of translational potential.
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影响因子：
20.1
作者：
Donato AJ;Machin DR;Lesniewski LA
通讯作者：
Lesniewski LA
影响因子：
16.6
作者：
Mammoto, Akiko;Mammoto, Tadanori;Ingber, Donald E.
通讯作者：
Ingber, Donald E.
DOI：
10.1073/pnas.0800835105
发表时间：
2008-08-12
影响因子：
11.1
作者：
Ghosh, Kaustabh;Thodeti, Charles K.;Ingber, Donald E.
通讯作者：
Ingber, Donald E.
影响因子：
4.1
作者：
Kotliar, Konstantin E.;Baumann, Marcus;Lanzl, Ines M.
通讯作者：
Lanzl, Ines M.
影响因子：
4.1
作者：
Browning, AC;Gray, T;Amoaku, WM
通讯作者：
Amoaku, WM