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