CCN2 deficiency in smooth muscle cells triggers cell reprogramming and aggravates aneurysm development

Area of Science:

• Vascular biology
• Cellular signaling
• Aortic disease pathogenesis

Background:

• Vascular smooth muscle cell (SMC) phenotypic switching is crucial in aortic aneurysm development.
• Cellular communication network factor 2 (CCN2) has context-dependent roles in disease.
• The specific function of SMC-CCN2 in abdominal aortic aneurysm (AAA) remains unclear.

Purpose of the Study:

• To investigate the role of SMC-specific CCN2 in AAA pathogenesis.
• To elucidate the molecular mechanisms by which CCN2 influences SMC phenotype and AAA.

Main Methods:

• Generation of SMC-specific CCN2 knockout (CCN2-KO) mice.
• Induction of AAA using angiotensin II (Ang II) infusion in hypercholesterolemic mice.
• AAA induction using elastase-β-aminopropionitrile.
• Analysis of SMC marker expression and TGF-β signaling pathways.

Main Results:

• SMC-restricted CCN2 deficiency led to AAA formation in mice.
• Loss of CCN2 in SMCs abrogated resistance to Ang II-induced AAA.
• CCN2 deficiency altered SMC marker expression and reprogramed SMCs, involving Krüppel-like factor 4.
• CCN2 was found to intersect with TGF-β signaling.

Conclusions:

• SMC-CCN2 is a novel regulator of SMC phenotypic switching.
• CCN2 deficiency in SMCs promotes AAA development through SMC reprogramming.
• Targeting SMC-CCN2 may offer a therapeutic strategy for AAA.