Angiopoietin/Tie2 signalling and its role in retinal and choroidal vascular diseases: a review of preclinical data

Figures

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  Fig. 1. Angiogenic cascade. Steps in the angiogenic cascade: formation of a stable mature vascular network requires vessel sprouting, maturation and vessel remodelling. The collective migration of ECs is led by a Tie2lo tip cell that guides the Tie2hi stalk cells to elongate a vessel in response to a VEGF gradient. VEGF/VEGFR2/3 signalling in tip cells induces Dll4 expression in these cells, which then signals via Notch1 in stalk cells to downregulate VEGFR2/3, thereby inhibiting tip cell fate in stalk cells. Migrating tip cells anastomose with tip cells from neighbouring sprouts, while the trailing stalk cells proliferate to elongate the sprout and form a vascular lumen. Following perfusion of these vessels, ECs gain stability and form a monolayer of quiescent phalanx cells connected by vascular endothelial cadherin and claudins. Formation of a basement membrane and recruitment of mural cells (SMCs and pericytes) occurs in a process regulated by PDGF/PDGFRβ, Ang-1/Tie2 and TGF-β signalling, stabilising the vasculature. Cells are not represented to scale. Ang-1 angiopoietin-1, Dll4 delta-like 4, EC endothelial cell, PDGF platelet-derived growth factor, PDGFRβ platelet-derived growth…

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  Fig. 2. Ang/Tie signalling pathway under physiological and pathophysiological conditions. The Ang/Tie pathway regulates vascular stability under physiological and pathological conditions. The receptor components of the Ang/Tie pathway, Tie1 and Tie2, are expressed primarily in the endothelium. In a healthy vessel (left), Ang-1/Tie2 signalling at cell–cell junctions leads to downstream activation of the PI3K/AKT pathway and induction of eNOS and survivin, leading to EC survival. Tie2-mediated phosphorylation of FOXO1 prevents its nuclear translocation, inhibiting transcription of its target genes, including Ang-2, while inhibition of NFκB cells suppresses the expression of inflammatory genes such as ICAM-1, VCAM-1 and E-selectin. Ang-1/Tie2 signalling via GTPase pathways (Rac1/Rap1 or Iqgap1/Rap1) results in cortical actin cytoskeleton stabilisation. In migrating ECs, Tie2 is localised at the cell–extracellular matrix contacts and preferentially activates ERK signalling. Recruitment of adaptor proteins such as DOKR and GRB2 to the Tie2 receptor supports PI3K-mediated EC migration. Overall, Ang-1/Tie2 signalling and its downstream effects promote EC integrity, contributing to vascular…

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  Fig. 3. Retinal and choroidal vasculatures, inner and outer BRB. The retinal vasculature supplies the inner two-thirds of the retina, and the exchange of nutrients with the retinal tissue is highly regulated by the inner BRB, formed by tight junctions connecting retinal capillary ECs. The inner BRB is covered by astrocytes, Müller cells and a high density of pericytes. The choroidal vasculature supplies the outer one-third of the retina. The choriocapillaris is fenestrated and has low pericyte coverage. Tight junctions connecting the RPE cells form the outer BRB. Cells are not represented to scale. BRB blood–retinal barrier, EC endothelial cell, RPE retinal pigment epithelium, VE-cadherin vascular endothelial cadherin.

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  Fig. 4. Overview of the effects of dual Ang-2/VEGF-A inhibition in nAMD and DR. Retinal and choroidal vasculatures in a healthy eye (left), an eye with nAMD (middle) and an eye with DR (right). Ang-2 and VEGF-A synergistically drive vascular leakage, inflammation and neovascularisation of choroidal vessels in nAMD, and neovascularisation and abnormal permeability of retinal vessels in DR. Data from preclinical studies suggest that combined blockade of Ang-2 and VEGF-A could act synergistically to reduce these effects, improving outcomes in retinal and choroidal diseases. Cells are not represented to scale. AMD age-related macular degeneration, Ang-1 angiopoietin-1, Ang-2 angiopoietin-2, BRB blood–retinal barrier, DR diabetic retinopathy, nAMD neovascular age-related macular degeneration, RPE retinal pigment epithelium, VEGF vascular endothelial growth factor, VEGF-A vascular endothelial growth factor-A.