Diabetes-related changes in the protein composition and the biomechanical properties of human retinal vascular basement membranes

Abstract

Basement membranes (BMs) are specialized sheets of extracellular matrix that outline epithelial cell layers, muscle fibers, blood vessels, and peripheral nerves. A well-documented histological hallmark of progressing diabetes is a major increase in vascular BM thickness. In order to investigate whether this structural change is accompanied by a change in the protein composition, we compared the proteomes of retinal vascular BMs from diabetic and non-diabetic donors by using LC-MS/MS. Data analysis showed that seventeen extracellular matrix (ECM)–associated proteins were more abundant in diabetic than non-diabetic vascular BMs. Four ECM proteins were more abundant in non-diabetic than in diabetic BMs. Most of the over-expressed proteins implicate a complement-mediated chronic inflammatory process in the diabetic retinal vasculature. We also found an up-regulation of norrin, a protein that is known to promote vascular proliferation, possibly contributing to the vascular remodeling during diabetes. Many of the over-expressed proteins were localized to microvascular aneurisms. Further, the overall stoichiometry of proteins was changed, such that the relative abundance of collagens in BMs from diabetic patients was higher than normal. Biomechanical measurements of vascular BM flat mounts using AFM showed that their outer surface was softer than normal.

Early Changes of Blood Flow Parameters of Ophthalmic Artery in Patients with Type 1 Diabetes Mellitus

“…Increased vascular resistance is a consequence of changes in vascular structure. Thickening of the basement membrane, protein composition changes, and hyaline deposition are initial changes seen in the capillaries at the early stages of DM (12). Consistent with our findings, Romney et al (4) noted that vascular compliance was reduced in both large and small arteries in type 1 DM before clinically apparent microvascular complications.…”

“…DR is a consequence of microvascular disorder and altered insulin metabolism; it causes significant histopathological changes in the ocular vascular structure, such as endothelial changes, loss of pericytes, a narrowed vessel lumen, and a thickened basement membrane (12,13). Therefore, it is not clear when the vascular structure and related ocular hemodynamic parameters begin to change.…”

To form and function: on the role of basement membrane mechanics in tissue development, homeostasis and disease

“…Conversely, the outer surface of vascular BMs has been shown to soften as a result of diabetes, despite the increase in their collage IV levels [102]. Although collagen IV levels may not necessarily be indicative of stiffness, as evidenced by the fact that the eye capsule with higher collagen IV levels is softer than the ILM [102], an increase in collagen IV levels in the same BM often results in higher stiffness (as discussed in §4.2). Therefore, it is yet to be understood why the vascular BMs soften and whether the same softening pattern is observed in the inner (i.e.…”

Comprehensive Endogenous Tagging of Basement Membrane Components Reveals Dynamic Movement within the Matrix Scaffolding

“…More than 20 distinct human diseases are associated with genetic disruption of BM components, highlighting the diverse and important roles of BMs (Nyströ m et al, 2017). The misregulation of BM component expression is also a key driver of cancer metastasis, and defective BM turnover leads to tissue decline in diabetes mellitus, fibrosis, and aging (Candiello et al, 2010;Halfter et al, 2017;Naba et al, 2014).…”