Integral role for lysyl oxidase-like-1 in conventional outflow tissue function and behavior.
Integral role for lysyl oxidase-like-1 in conventional outflow tissue function and behavior.
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DOI：
10.1096/fj.202000702rr
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发表时间：
2020-08
期刊：
影响因子：
--
通讯作者：
Stamer WD
中科院分区：
文献类型：
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作者：
Li G;Schmitt H;Johnson WM;Lee C;Navarro I;Cui J;Fleming T;Gomez-Caraballo M;Elliott MH;Sherwood JM;Hauser MA;Farsiu S;Ethier CR;Stamer WD
赖氨酰氧化酶样-1（LOXL 1）是维持弹性蛋白纤维的重要交联酶，对弹性血管和组织的稳定性和强度至关重要。LOXL 1基因座的变异与剥脱综合征（一种全身性纤维性病变）风险的急剧增加相关，剥脱综合征通常表现为高眼压和剥脱性青光眼。我们研究了LOXL 1在传统流出功能中的作用，这是眼内压的主要调节器。使用Loxl 1 −/−，Loxl 1 +/−和Loxl 1 +/+小鼠，我们观察到LOXL 1表达与眼内压之间的负相关关系，随着年龄的增长而恶化。Loxl 1 −/−小鼠的眼内压升高与更大的地球仪、眼顺应性降低、流出功能增加、细胞外基质异常和巩膜内静脉扩张相关，但动脉或毛细血管没有扩张。有趣的是，在活体Loxl 1 −/−小鼠眼中，当眼内压急性升高时，Schlemm管不太容易塌陷，这表明巩膜外静脉压升高。因此，LOXL 1表达是正常眼内压控制所必需的，而消融导致细胞外基质修复/稳态和常规流出生理学改变。Schlemm管和远端静脉扩张，而不是动脉扩张，与弹性蛋白在低压血管中受到周期性机械应力的关键结构和功能作用一致。
Lysyl oxidase like-1 (LOXL1), a vital crosslinking enzyme in elastin fiber maintenance, is essential for the stability and strength of elastic vessels and tissues. Variants in the LOXL1 locus associate with a dramatic increase in risk of exfoliation syndrome, a systemic fibrillopathy, which often presents with ocular hypertension and exfoliation glaucoma. We examined the role of LOXL1 in conventional outflow function, the prime regulator of intraocular pressure. Using Loxl1−/−, Loxl1+/− and Loxl1+/+ mice, we observed an inverse relationship between LOXL1 expression and intraocular pressure, which worsened with age. Elevated intraocular pressure in Loxl1−/− mice was associated with a larger globe, decreased ocular compliance, increased outflow facility, extracellular matrix abnormalities, and dilated intrascleral veins, yet no dilation of arteries or capillaries. Interestingly, in living Loxl1−/− mouse eyes, Schlemm’s canal was less susceptible to collapse when challenged with acute elevations in intraocular pressure, suggesting elevated episcleral venous pressure. Thus, LOXL1 expression is required for normal intraocular pressure control, while ablation results in altered extracellular matrix repair/homeostasis and conventional outflow physiology. Dilation of Schlemm’s canal and distal veins, but not arteries, is consistent with key structural and functional roles for elastin in low-pressure vessels subjected to cyclical mechanical stress.