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

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.

A Pilot Study on MicroRNA Profile in Tear Fluid to Predict Response to Anti-VEGF Treatments for Diabetic Macular Edema

“…In good responders, the VEGF and Notch signaling pathways were targeted by the miRNAs ( Figure 5 ), and these pathways have been described to interact dynamically at the cellular level to control the vascular network [ 45 ].…”

“…The Notch pathway regulates developmental angiogenesis as well as post-angiogenic blood vessel remodeling and homeostasis [ 45 , 50 ]. Elevated Notch1 ligands are present in the vitreous of a subset of patients with DME [ 50 ].…”

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“…One EC differentiates into a tip cell, expressing VEGFR2, and is characterized by the presence of filopodia stretched into the tissue, that can sense and follow a gradient of chemoattractant, such as a growth factor ( Figure 3 regulated through VEGF and VEGFR-2; the mechanism through which only the first cell acquires the phenotype of tip cell is through the signaling pathway of DLL4-NOTCH1, that in stalk cells gives rise to a cleavage product which acts as a transcription factor downregulating VEGFR2, 3 and NRP-1, and upregulating VEGFR1 and soluble VEGFR1 93,94,95 . The lumen forms in a process influenced by many factors and by the blood flow itself, through apoptosis and through the confluence of intracellular vacuoles that form in EC in response to integrin signaling pathway [96][97][98] .…”