Complement proteins C3 and C4 bind to collagen and elastin in the vascular wall: a potential role in vascular...

Area of Science:

• Vascular Biology
• Immunology
• Cardiovascular Research

Background:

• Circulating inflammatory mediators, including complement activation products, are implicated in cardiovascular disease pathogenesis.
• Complement proteins have been found in atherosclerotic plaques and on the luminal surface of blood vessels.
• An unexpected observation revealed complement protein deposition along the external elastic lamina of mouse aortas, independent of luminal deposition or plaque.

Purpose of the Study:

• To investigate the hypothesis that complement activation in the adventitia, rather than the endothelium, plays a critical role in vascular stiffness and atherosclerosis.
• To ultrastructurally identify the binding targets of complement components C3 and C4 within the adventitia of the mouse aorta.

Main Methods:

• Ultrastructural identification of complement component binding targets.
• Analysis of mouse aortas from ApoE(-/-) and C57Bl/6J control mice.
• Examination of perivascular adipose tissue.

Main Results:

• Extensive binding of C3 and C4 to collagen and elastin fibers within the adventitia was observed in both mouse models.
• C3 and C4 were also found within the perivascular adipose tissue.
• Complement deposition occurred in the absence of luminal deposition or plaque development.

Conclusions:

• Complement activation may contribute to vascular stiffness and atherosclerosis via an "outside-in" mechanism originating in the adventitia.
• Perivascular adipose tissue may produce C3 and C4, which then bind to adventitial collagen and elastin.
• This binding, potentially via covalent thiolester bonds, could lead to increased vascular stiffness.