Höh, Alexandra E; (2024) Effect Of Leucine-Rich Α-2 Glycoprotein 1 on ocular vessel maturation and normalization. Doctoral thesis (Ph.D), UCL (University College London).

Text Thesis AHoeh FINAL 2024-02-20.pdf - Accepted Version Access restricted to UCL open access staff until 1 March 2025. Download (19MB)

Abstract

Developmental angiogenesis leads to the formation of an organized network of functional and stable vessels. In contrast, neovascularization in disease is characterized by vessels which are immature and leaky, have poor pericyte coverage, alterations of the basement membrane deposition and grow in a chaotic pattern. The secreted glycoprotein leucine-rich alpha-2-glycoprotein-1 (LRG1) is induced in many diseases where it contributes to the growth of pathogenic neovascularization. In contrast, Lrg1 gene expression is not upregulated in developmental angiogenesis and Lrg1 knockout does not significantly affect the developmental vascularization of the retina. This thesis investigates if introducing exogenous LRG1 impairs developmental angiogenesis and drives vessel development towards an abnormal and dysfunctional phenotype. To test this, mouse pups were intravitreally injected with either LRG1 protein or a LRG1 overexpression vector. In addition, it was examined if antibody blockade of LRG1 or Lrg1 knockout allows normalization of vessel structure and function in mouse models of pathogenic angiogenesis including oxygen-induced retinopathy (OIR) and spontaneous subretinal neovascularization in very low density lipoprotein receptor (Vldlr) knockout and JR5558 (rnv3) mice. Introduction of LRG1 during developmental vascularization of the retina caused structural and functional vascular abnormalities, especially a reduction of pericyte coverage and expression of pericytic NG2, impaired basement membrane deposition and increased leakage at the vascular front as a result of higher levels of transcytotic activity. Accordingly, knockout of Lrg1 reduced the number of neovascular tufts and improved NG2 expression in pericytes of the pathogenic neovascular vessels in the OIR model, but LRG1 inhibition or knockout failed to show any effect on lesion number or vascular structure in Vldlr knockout and JR5558 mice where underlying genetic mutations drive the growth of pathogenic vessels. The presented evidence supports the hypothesis that LRG1 is a vascular disrupting factor which impairs vessel maturation and stabilization, and that LRG1 inhibition has therapeutic potential in diseases characterized by abnormal vessel growth and remodelling without underlying genetic mutation.

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