The Role of Dll4/Notch Signaling in Normal and Pathological Ocular Angiogenesis: Dll4 Controls Blood Vessel Sprouting and Vessel Remodeling in Normal and Pathological Conditions - PubMed (original) (raw)
Review
. 2018 Jul 5:2018:3565292.
doi: 10.1155/2018/3565292. eCollection 2018.
Affiliations
- PMID: 30116629
- PMCID: PMC6079472
- DOI: 10.1155/2018/3565292
Review
The Role of Dll4/Notch Signaling in Normal and Pathological Ocular Angiogenesis: Dll4 Controls Blood Vessel Sprouting and Vessel Remodeling in Normal and Pathological Conditions
Ivan Lobov et al. J Ophthalmol. 2018.
Abstract
Background: Retina is the highest oxygen-demanding and vascularized tissue in the body. Retinal development and function require proper vascularization and blood vessel function and integrity. Dll4 is most prominently expressed in the endothelium of angiogenic blood vessels and in quiescent arteries and capillaries in all tissues and organs of the mammalian species, and it is the key regulator of blood vessel sprouting.
Results: Dll4 is a transmembrane protein that acts as a ligand for Notch receptors 1 and 4. Genetic deletion of Dll4 causes severe abnormalities in embryonic and postnatal vascular development. Deletion of even a single Dll4 allele results in almost complete embryonic lethality due to severe vascular abnormalities, the phenomenon called haploinsufficiency indicating the critical role of Dll4/Notch in vascular development. Dll4/Notch pathway interplays at multiple levels with other signaling pathways including VEGF, Wnt/Fzd, and genes controlling vascular toning. Multiple studies of the effects of Dll4 inhibition were performed in the developing retina to elucidate the key functions of Dll4 in normal and pathological angiogenesis. Several genetic approaches and therapeutic molecules were tested to evaluate the biological and therapeutic effects of acute and prolonged Dll4 inhibition in the eye and oncology.
Conclusions: All current studies demonstrated that Dll4 controls blood vessel sprouting, growth, and remodeling in normal and pathological conditions as well as arterial-venous differentiation. Genetic and therapeutic Dll4 modulation studies show that Dll4 inhibition can promote blood vessel sprouting and might be useful to stimulate vessel growth in the ischemic retina and Dll4 is the key modulator of the postangiogenic vascular remodeling that ultimately defines vascular patterning.
Figures
Figure 1
Dll4/Notch signaling in the endothelial cells. Notch receptor activation by Dll and Jagged ligands expressed by the neighboring cells leads to the cleavage of the intracellular domain (NICD) of the receptor, its translocation into the nucleus, and blockade of CSL that allows the transcription activation of the downstream genes by transcription factors of Hes and Hey families [14].
Figure 2
Retinal blood vessel development in the mouse eye. Retinal blood vessels start to grow at the postnatal day 1 (P1) from the optic nerve head in the center of the retina and extend toward periphery and achieve the retinal periphery by P8. At P3, developing vasculature covers approximately 30% of the retina (a), but by P6, about 70–80% of the retina is covered by the developing vessels (b). Angiogenic sprouts at the growing front of the developing vasculature have multiple filopodia extending from the tip cells (c). GS lectin staining: 2x magnification (a, b); 10x magnification (c). At the same time, there is an ongoing regression of the hyaloid vessels [30, 31]. Remaining hyaloid blood vessels are labelled by asterisks.
Figure 3
Dll4/lacZ expression in the developing mouse retina of Dll4+/− heterogeneous mice at P7 (a, b) and P8 (c). Dll4 is predominantly expressed in the capillaries at the growing front of the developing retinal vasculature and differentiated arteries (red dots) but not veins (blue dots) at P7 (b) and at P8 (c). X-gal staining: 2x (a) and 4x (b, c) magnification [33].
Figure 4
Retinal vascular development in normal (WT) (a) and Dll4-deficient heterozygous mice (Dll4+/−) (b) at P6. Heterozygous Dll4 deletion causes severe developmental retinal vascular abnormalities leading to the increased blood vessel sprouting and formation of a syncytium-like vascular plexus (yellow arrowheads). 4x magnification. GS lectin staining. [33].
Figure 5
Pathological neovascularization in OIR (oxygen-induced retinopathy model) at P16 and Dll4 expression in OIR at P16. Dll4 is expressed in the capillaries, arteries (a), and pathological neovascular tufts (yellow arrows) in OIR in pathological angiogenesis but at a lower level in veins (V). X-gal staining: 4x (a, c) and 10x (b, d, e) magnification. Yellow arrows indicate pathological neovascular tufts.
Figure 6
Pharmacological inhibition of Dll4 in OIR using soluble Dll4-Fc fusion protein (b) ameliorates pathological retinal neovascularization and improves normal retinal revascularization in the OIR model [33]. Yellow arrows indicate pathological neovascular tufts.
Figure 7
Pharmacological inhibition of Dll4 in acute hyperoxia (6 hours, 75% O2) using soluble Dll4-Fc fusion protein (b) ameliorates pathological retinal capillary nonperfusion compared to Fc control (a). GS lectin-positive and tomato lectin-negative capillaries are transiently nonperfused. Small white arrows indicate nonperfused capillary segments (b). Nonperfused capillaries rapidly regress within 24 hours. Note large nonperfused areas in the control retinas and just a few individual nonperfused segments in Dll4-Fc-treated retinas. Green: GS lectin staining; red: tomato lectin perfusion [51].
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