Molecular Insights of Gpr126 Signalling in the Angiogenesis and Pathology of Ischaemic Stroke

Kakogiannos, Nikolaos (2021). Molecular Insights of Gpr126 Signalling in the Angiogenesis and Pathology of Ischaemic Stroke. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.00012507

Abstract

The blood-brain barrier (BBB) and blood-retinal barrier (BRB) are highly specialized vascular regions of the central nervous system that control the transfer of substances and cells from the blood to these tissues. Although Wnt/β-catenin signalling is essential for BBB development, its downstream targets within the neurovasculature remain poorly understood.

Microarray analysis was performed to identify targets of Wnt/βcatenin signalling that underlie BBB maturation. Gpr126 was revealed as a novel Wnt/β-catenin–regulated gene in mouse brain endothelial cells. Gpr126 is progressively expressed in early post-natal life during BBB establishment, and it decreases in normal adult tissue, when the BBB has matured. Endothelial genetic ablation of Gpr126 delays BBB maturation, as shown by significant reduction of the majority of mature BBB marker genes and increased permeability of the brain cortex microcirculation. Furthermore, in the developing vasculature of the retina, the absence of Gpr126 delays angiogenesis and decreases the number of tip cells and the vascular density, while in the adult, this causes artery–vein crossover. Indeed, in-vitro data support a positive role for Gpr126 in angiogenesis through regulation of endothelial cell proliferation and migration. Mechanistically, I show that Gpr126 is part of a complex that includes lowdensity lipoprotein-receptor-related protein 1 (Lrp1) and α3β1 integrin, two proteins involved in angiogenesis. Moreover, I provide evidence for reciprocal transcriptional and protein regulation between the expression of Gpr126 and Lrp1.

Finally, the absence of Gpr126 makes the endothelium refractory to lipopolysaccharide-induced inflammation, and improves recovery of the central nervous system in the pathology of ischaemic stroke. However, the molecular mechanisms here remain to be defined.

In summary, this study unravels novel roles for endothelial Gpr126 signalling in the physiological development of the BBB and BRB, and it suggests that Gpr126 inhibition represents a potential co-treatment for ischaemic stroke.

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