Elastase-2 deletion prevents vascular remodeling and abdominal aortic aneurysm development in a mice model induced by angiotensin II.

Abdominal aortic aneurysm (AAA) involves the remodeling of the aortic wall extracellular matrix (ECM), compromising biomechanical support and increasing the risk of aortic dissection and rupture. Activation of the renin-angiotensin system (RAS), particularly the synthesis of angiotensin II (Ang II), plays a fundamental role in AAA initiation and progression. Elastase-2 (ELA-2), a chymotrypsin-like serine protease, contributes to tissue Ang II generation and may be a key player in AAA pathophysiology. This study investigated the effects of ELA-2 deletion in a murine model of angiotensin II-induced AAA, with particular focus on determining whether ELA-2 modulates vascular contractility and aortic relaxation in wild-type mice and whether these effects are absent in ELA-2 knockout mice. We additionally examined the cellular alterations within the aortic wall that contribute to increased reactive oxygen species generation during AAA development. Male C57BL/6 J (wild-type, WT) and ELA-2 knockout (ELA-2KO) mice, aged 10 to 15 weeks, were infused with Ang II (1500 ng/kg/min) for 28 days to induce AAA formation. Wild-type (WT) mice developed AAA, as evidenced by aortic dilation, structural remodeling, fibrosis, and inflammation. In contrast, ELA-2KO mice showed markedly reduced pathological changes following Ang II-induced AAA. Histological and biochemical analyses of the abdominal aorta revealed enhanced gelatinolytic activity, macrophage infiltration, and oxidative stress in WT mice, all of which were significantly attenuated in ELA-2KO mice. Furthermore, transcriptional profiling demonstrated that ELA-2 deletion maintained a contractile VSMC phenotype, suggesting a protective effect against maladaptive vascular remodeling. In summary, ELA-2 deficiency prevented Ang II- induced AAA formation and pathological vascular remodeling, highlighting its potential as a therapeutic target to mitigate AAA progression.