Ccn2 deletion predisposes to aortic aneurysm formation and death in mice which is partially reduced by mineralocorticoid receptor antagonist treatment

Background and Purpose: Cellular Communication Network Factor 2 (CCN2) is a matricellular protein normally present in the vascular wall but overexpressed in several cardiovascular diseases. CCN2 has been proposed as a downstream mediator of profibrotic actions of Transforming Growth Factor (TGF)-β and Angiotensin II (Ang II). However, its direct role in cardiovascular diseases is not completely understood. Experimental Approach: To investigate the direct role of CCN2 under vascular pathological conditions, a conditionally deficient CCN2 (CCN2-KO) mouse was evaluated infused or not with Ang II. Key Results: In the absence of CCN2, Ang II infusion induced a rapid (within 48 hours) aortic aneurysm generation and increased aneurysm rupture with 80 % lethality at the endpoint. CCN2 deletion caused elastin layer disruption and increased metalloproteinase activity, which were aggravated by Ang II administration. Aortic RNA-seq studies and the subsequent Gene Ontology enriched analysis pointed out the aldosterone biosynthesis process as one of the most enriched terms in absence of CCN2. Pharmacological aldosterone pathway intervention in Ang II-infused CCN2-KO mice, by treatment with the mineralocorticoid receptor antagonist spironolactone, reduced aneurysm formation and mortality after Ang II infusion. Conclusion and Implications: CCN2 deletion induces a rapid aneurysm formation and rupture after Ang II infusion which is partially prevented by blocking the mineralocorticoid receptor. Our present data highlight, for the first time, the potential role of CCN2 as a vascular homeostatic factor and its relevance in the aldosterone synthesis, opening new avenues to future studies in aortic aneurysm treatment.