Blood Vessel Basement Membrane Alterations in Human Retinal Microaneurysms During Aging
Blood Vessel Basement Membrane Alterations in Human Retinal Microaneurysms During Aging
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DOI：
10.1167/iovs.16-19998
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发表时间：
2017-02-01
影响因子：
4.4
通讯作者：
Ruberte, Jesus
中科院分区：
文献类型：
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作者：
Lopez-Luppo, Mariana;Nacher, Victor;Ruberte, Jesus
目的.微动脉瘤被认为是视网膜血管疾病的标志，存在于老年视网膜中。在这里，人视网膜微动脉瘤的基底膜已在老化过程中进行了分析。从17个非糖尿病供体获得视网膜。用抗血液基底膜主要成分的抗体对整个视网膜和石蜡切片进行免疫化学标记。还进行了胰蛋白酶消化和透射电子显微镜检查。小的微动脉瘤表现为IV型胶原、层粘连蛋白、纤连蛋白、巢蛋白和串珠素表达增加，沿着基底膜增厚。出乎意料的是，在小的微动脉瘤中发现了III型胶原的交联原纤维，这是视网膜毛细血管中不存在的一种胶原。这与赖氨酰氧化酶样（LOXL）2和4的表达增强平行。大的微动脉瘤表现为基底膜蛋白质含量减少和结构紊乱。这与基质金属蛋白酶（MMP）-9和纤溶酶原激活物抑制剂（派）-1的表达增加相伴随。小微血管和大微血管的周细胞覆盖率下降。可能由募集的周细胞产生的基质蛋白积聚导致的小微动脉瘤基底膜增厚，以及可能由于LOXL 2和LOXL 4的作用导致的交联胶原III原纤维的出现，可以被认为是在微动脉瘤形成的早期阶段加强血管壁的补偿机制。随后，MMP-9和PAI-1活性增加，分别导致血液基底膜破裂和微血栓扩张，以及周细胞损失，导致血管壁弱化，可以解释在微动脉瘤形成晚期观察到的血管壁扩张。
PURPOSE. Microaneurysms, considered a hallmark of retinal vascular disease, are present in aged retinas. Here, the basement membrane of human retinal microaneurysms has been analyzed during aging.METHODS. Retinas were obtained from 17 nondiabetic donors. Whole mount retinas and paraffin sections were marked immunohistochemically with antibodies against the main components of the blood basement membrane. Trypsin digestion and transmission electron microscopy also were performed.RESULTS. Small microaneurysms presented increased expression of collagen IV, laminin, fibronectin, nidogen, and perlecan, along with basement membrane thickening. Unexpectedly, crosslinked fibrils of collagen III, a type of collagen absent in retinal capillaries, were found specifically in small microaneurysms. This was parallel to enhanced lysyl oxidase-like (LOXL) 2 and 4 expression. Large microaneurysms showed diminution of protein content, as well as disorganization, in their basement membrane. This was concomitant with an increased expression of matrix-metalloproteinase (MMP)-9 and plasminogen activator inhibitor (PAI)-1. Pericyte coverage declined between small and large microaneurysms.CONCLUSIONS. Thickening of the basement membrane in small microaneurysms by accumulation of matrix proteins probably produced by recruited pericytes, together with the appearance of crosslinked collagen III fibrils probably due to the action of LOXL2 and LOXL4, could be considered as compensatory mechanisms to strengthen the vascular wall in the early phase of microaneurysm formation. Later, increased activity of MMP-9 and PAI-I, which produce disruption of the blood basement membrane and expansion of microthrombi respectively, and loss of pericytes, which produces weakening of the vascular wall, could explain the wall dilation observed in the late phase of microaneurysm formation.