LRG1 Alters Pericyte Phenotype and Compromises Vascular Maturation

TL;DR

LRG1 disrupts retinal blood vessel development, leading to weaker and leakier blood vessels, suggesting it could be a target for treating diseases with abnormal blood vessel growth.

Contribution

The study demonstrates that LRG1 interferes with vascular maturation in retinal development, identifying it as a potential therapeutic target for angiopathy-related diseases.

Findings

Exogenous LRG1 reduces pericyte coverage and NG2 expression in retinal blood vessels.

LRG1 compromises collagen IV sheathing and reduces vessel calibre and vascular density.

LRG1 increases blood-retinal barrier permeability and transcytotic vesicles in endothelial cells.

Abstract

Upregulation of leucine-rich alpha-2-glycoprotein-1 (LRG1) contributes to aberrant neovascularization in many different diseases. In contrast, LRG1 is not involved in developmental angiogenesis. Here, we investigated the vasculopathic properties of LRG1 by examining its effect on developing retinal blood vessels. By injecting recombinant protein or an expression vector into the mouse retina during vascular development, we showed that exogenous LRG1 reduces pericyte coverage and NG2 expression. It leads to diminished collagen IV sheathing, fewer adhesion and gap junctions, and reduced vessel calibre and vascular density. Moreover, in mouse retinae containing exogenous LRG1, the developing blood–retinal barrier remains more permeable with significantly higher numbers of transcytotic vesicles present in microvascular endothelial cells. These results reveal that exogeneous LRG1 is sufficient to interfere with the maturation of developing retinal vessels and drive vessel development towards a dysfunctional phenotype. These observations deliver further evidence that LRG1 is an angiopathic factor and highlight the therapeutic potential of blocking LRG1 in diseases characterized by pathogenic angiogenesis or vascular remodelling.

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