Endothelial cells-targeted soluble human Delta-like 4 suppresses both physiological and pathological ocular...

Area of Science:

• Vascular Biology and Medicine
• Molecular and Cellular Biology
• Ophthalmology

Background:

• The Notch pathway plays a critical role in angiogenesis, making it a key therapeutic target for pathologic angiogenesis.
• While Notch signal modulation can impede angiogenesis, activation is considered more promising due to risks associated with long-term blockage, such as vessel neoplasm.
• Development of an efficient, in vivo deliverable Notch ligand for therapeutic applications remains a challenge.

Purpose of the Study:

• To develop a novel, soluble Notch ligand with high Notch-activating capacity for targeting angiogenesis.
• To evaluate the efficacy of the novel ligand in suppressing angiogenesis both in vitro and in vivo.

Main Methods:

• Generation of a novel soluble Notch ligand, hD4R, comprising the Delta-Serrate-Lag-2 fragment of human Delta-like4 (Dll4) and an RGD motif for endothelial cell (EC) targeting.
• Assessment of hD4R binding to ECs and its ability to trigger Notch signaling.
• In vitro assays (network formation, sprouting) and in vivo models (neonatal retinal angiogenesis, laser-induced choroidal neovascularization - CNV) to evaluate anti-angiogenic effects.

Main Results:

• The novel hD4R ligand effectively binds to ECs via its RGD motif and activates Notch signaling.
• hD4R demonstrated significant suppression of angiogenesis in vitro, as evidenced by reduced network formation and sprouting.
• In vivo studies confirmed that hD4R efficiently repressed neonatal retinal angiogenesis and laser-induced CNV.

Conclusions:

• A novel, in vivo deliverable Notch ligand, hD4R, has been successfully developed.
• hD4R exhibits potent anti-angiogenic properties, suppressing excessive blood vessel formation both in vitro and in vivo.
• hD4R represents a promising therapeutic strategy for managing angiogenesis-related diseases, including CNV.