The disruptive role of LRG1 on the vasculature and perivascular microenvironment

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  Figure 1. Cell source, target cells and outcome of LRG1 in the vasculature. LRG1 is expressed constitutively by only a few cell types, including hepatocytes and neutrophils, but during disease can be induced in various other cells. In the vasculature, endothelial cells are the only source of LRG1, but other local cells may also be induced to express LRG1 such as fibroblasts and tumor cells. Irrespective of the source, LRG1 affects the function of all cellular components of blood vessels resulting in vascular damage. Vascular dysfunction is closely associated with fibrosis, and both may influence each other through LRG1 signaling. EndMT, endothelial to mesenchymal transition. Created with BioRender.com.

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  Figure 2. Induction of LRG1. (A) Schematic representation of inflammatory factors reported to activate LRG1 gene expression and known transcriptional and post-transcriptional regulatory mechanisms. Cytokines and lipopolysaccharide (LPS) acting through their cognate receptors and downstream transcription factors drive LRG1 gene induction. lncRNA TUG1 facilitates LRG1 transcription while miR-335, miR-494, miR-497, miR-150-5p and miR-24-3p promote the degradation of LRG1 mRNA. LRG1 protein is differentially glycosylated in a cell- and function-specific manner that may affect its activity. The secreted protein may combine to form dimers and trimers. OSM, oncostatin M; IL, interleukin; TLR4, toll-like receptor 4; lncRNA, long non-coding RNA; miRNA, microRNA. (B) LRG1 is induced during cell damage and infection as part of the repair mechanism. In the presence of LRG1 and TGF-β, we propose that cells are activated and de-differentiated into a less mature state to enable wound healing. As inflammatory signals subside, LRG1 expression diminishes allowing resolution of tissue damage and cells to return to a quiescent state. (C) Under chronic conditions, inflammatory signals maintain LRG1 expression…

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  Figure 3. Drivers of vascular dysfunction and its therapeutic reversal. Vessels under normal conditions are stabilized and maintained in a mature functional state through cross-talk between the endothelial cell and mural cells (pericytes and smooth muscle cells). During disease, vasoactive factors are released that destabilize existing vessels and stimulate new dysfunctional vessel growth, both of which contribute to disease progression. Targeting factors that alter vascular function in disease is a common therapeutic objective. Inhibiting LRG1 activity has been shown to normalize vessels and may therefore be a promising therapeutic approach. DR, diabetic retinopathy; nAMD, neovascular age-related macular degeneration; CKD, chronic kidney disease. Created with BioRender.com.

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  Figure 4. LRG1 cell-dependent signaling and outcome. LRG1 can induce signaling in all cellular constituents of the vasculature. Depending on the configuration of signaling receptors and downstream influences, LRG1 can cause the TGF-β angiogenic switch through acting on the endothelial cell, pericyte and smooth muscle cell. LRG1 has been shown to alter the canonical and non-canonical TGF-β signaling pathways in a cell-dependent manner. EndMT, endothelial to mesenchymal transition; EMT, epithelial to mesenchymal transition. Created with BioRender.com.