Neuron-derived neurotrophic factor functions as a novel modulator that enhances endothelial cell function and...

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Regenerative Medicine

Background:

• Stimulating revascularization is crucial for treating cardiovascular diseases.
• Endothelial cells play a key role in blood vessel formation and repair.

Purpose of the Study:

• To identify novel secreted molecules that promote revascularization.
• To investigate the role of neuron-derived neurotrophic factor (NDNF) in endothelial cell function and ischemia-induced neovascularization.

Main Methods:

• Investigated NDNF secretion from human endothelial cells under hypoxic conditions.
• Assessed NDNF's effects on endothelial cell network formation and survival in vitro, focusing on Akt/eNOS signaling and integrin αvβ3.
• Utilized siRNA-mediated knockdown and intramuscular overexpression of NDNF in mouse models of limb ischemia.
• Evaluated the impact of NDNF on blood flow recovery, capillary density, and Akt/eNOS phosphorylation in ischemic limbs.
• Examined the role of endothelial nitric oxide synthase (eNOS) in mediating NDNF's effects.

Main Results:

• NDNF is upregulated in endothelial cells of ischemic limbs and secreted by human endothelial cells, with secretion stimulated by hypoxia.
• NDNF promotes endothelial cell network formation and survival in vitro via Akt/eNOS signaling involving integrin αvβ3.
• Overexpression of NDNF in mice enhances blood flow recovery and capillary density in ischemic limbs, associated with increased Akt and eNOS phosphorylation.
• NDNF's pro-angiogenic effects are dependent on eNOS activity, as demonstrated by studies with eNOS-deficient mice and NOS inhibition.
• Knockdown of NDNF impairs revascularization and Akt/eNOS signaling in response to ischemia.

Conclusions:

• NDNF functions as an endogenous factor that enhances endothelial cell function and promotes ischemia-induced revascularization through eNOS-dependent pathways.
• NDNF represents a potential therapeutic target for managing ischemic vascular disorders and promoting tissue repair.