Divergent Roles of Matrix Metalloproteinase 2 in Pathogenesis of Thoracic Aortic Aneurysm

Abstract

Objective— Aortic aneurysm, focal dilation of the aorta, results from impaired integrity of aortic extracellular matrix (ECM). Matrix metalloproteinases (MMPs) are traditionally known as ECM-degrading enzymes. MMP2 has been associated with aneurysm in patients and in animal models. We investigated the role of MMP2 in thoracic aortic aneurysm using 2 models of aortic remodeling and aneurysm. Approach and Results— Male 10-week-old MMP2-deficient (MMP2 −/− ) and wild-type mice received angiotensin II (Ang II, 1.5 mg/kg/day) or saline (Alzet pump) for 4 weeks. Although both genotypes exhibited dilation of the ascending aorta after Ang II infusion, MMP2 −/− mice showed more severe dilation of the thoracic aorta and thoracic aortic aneurysm. The Ang II–induced increase in elastin and collagen (mRNA and protein) was markedly suppressed in MMP2 −/− thoracic aorta and smooth muscle cells, whereas only mRNA levels were reduced in MMP2 −/− -Ang II abdominal aorta. Consistent with the absence of MMP2, proteolytic activities were lower in MMP2 −/− -Ang II compared with wild-type-Ang II thoracic and abdominal aorta. MMP2-deficiency suppressed the activation of latent transforming growth factor-β and the Smad2/3 pathway in vivo and in vitro. Intriguingly, MMP2 −/− mice were protected against CaCl 2 -induced thoracic aortic aneurysm, which triggered ECM degradation but not synthesis. Conclusions— This study reveals the dual role of MMP2 in ECM degradation, as well as ECM synthesis. Moreover, the greater susceptibility of the thoracic aorta to impaired ECM synthesis, compared with vulnerability of the abdominal aorta to aberrant ECM degradation, provides an insight into the regional susceptibility of the aorta to aneurysm development.