Complement C3a receptor-mediated vascular dysfunction: a complex interplay between aging and neurodegeneration

Area of Science:

• Neuroscience
• Immunology
• Vascular Biology

Background:

• Vascular dysfunction and compromised blood-brain barrier (BBB) integrity are hallmarks of aging and neurodegenerative diseases.
• The complement system, particularly the C3a/C3a receptor (C3a/C3aR) axis, plays a role in brain aging and disease, but its specific mechanisms in endothelial cells are unclear.

Purpose of the Study:

• To investigate the role of endothelial C3a/C3aR signaling in neurovascular inflammation and BBB permeability during normal aging and neurodegeneration.
• To elucidate the downstream molecular mechanisms linking C3aR signaling to BBB dysfunction.

Main Methods:

• Utilized normal, aged, and neurodegenerative mouse models.
• Examined endothelial C3aR signaling, VCAM1 expression, lymphocyte infiltration, and microglial activity.
• Assessed calcium release, VE-cadherin junction integrity, BBB permeability, and vascular structure.
• Employed C3aR knockout (C3ar1-/-) mice and C3aR antagonist treatment.

Main Results:

• Endothelial C3aR signaling promoted age-dependent VCAM1 increases, lymphocyte infiltration, and microglial activation.
• C3aR signaling induced calcium release, disrupting VE-cadherin junctions and increasing BBB permeability.
• Loss or inhibition of C3aR attenuated age-related microglial reactivity and neurodegeneration.

Conclusions:

• Complement-mediated C3aR signaling critically impacts vascular health and BBB function in aging and neurodegenerative conditions.
• Targeting the C3a/C3aR axis offers a potential therapeutic strategy for cerebral microvascular dysfunction.