TY - JOUR
T1 - Blood vessel basement membrane alterations in human retinal microaneurysms during aging
AU - López-Luppo, Mariana
AU - Nacher, Victor
AU - Ramos, David
AU - Catita, Joana
AU - Navarro, Marc
AU - Carretero, Ana
AU - Rodriguez-Baeza, Alfonso
AU - Mendes-Jorge, Luísa
AU - Ruberte, Jesús
N1 - Publisher Copyright:
© 2017 The Authors.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2017/2/1
Y1 - 2017/2/1
N2 - 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.
AB - 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.
KW - Aging
KW - Basement membrane
KW - Microaneurysm
KW - Retina
UR - http://www.scopus.com/inward/record.url?scp=85012277233&partnerID=8YFLogxK
U2 - 10.1167/iovs.16-19998
DO - 10.1167/iovs.16-19998
M3 - Article
C2 - 28196225
SN - 0146-0404
VL - 58
SP - 1116
EP - 1131
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
IS - 2
ER -