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

Vascular smooth muscle cell (VSMC) phenotypic switching is widely recognized as a key mechanism responsible for the pathogenesis of several aortic diseases such as aortic aneurysm. Cellular communication network factor 2 (CCN2), often upregulated in human pathologies and animal disease models, exerts a myriad of context-dependent biological functions. However, current understanding of the role of SMC-CCN2 in SMC phenotypic switching and its function in the pathology of abdominal aortic aneurysm (AAA) is lacking. Here we report the effect of SMC-restricted CCN2 deficiency of hypercholesterolemic mice on gene expression in infrarenal aorta with or without angiotensin II (Ang II)-infusion. CCN2-floxed mice were crossed with Myh11-Cre-ERT2 transgenic mice to generate male CCN2-floxed mice harboring SMC-specific Cre (CCN2fl/fl-Myh11-Cre-ERT2). Smooth muscle cell (SMC)-specific deletion of CCN2 was achieved by intraperitoneal (IP) injection of five consecutive doses of tamoxifen to 8 weeks old male CCN2fl/fl-Myh11-Cre-ERT2 mice. Age-matched male CCN2-floxed mice without Cre expression subjected to the same tamoxifen regimen were used as controls. After two-week washout period, SMC-specific CCN2-knockout mice, henceforth CCN2SMC∆ mice and CCN2-floxed control mice, henceforth CCN2fl/fl mice were used for the modeling of AAA (Ang II infusion via mini-osmotic pumps at the dose of 500 ng/kg/min for 7 days)