Extracellular Matrix Remodelling and Abdominal Aortic Aneurysm

Abstract

Aorta is the largest artery in the body. Aortic wall is comprised of an intricate arrangement of extracellular matrix (ECM) structural proteins, primarily collagen and elastin, and layers of vascular smooth muscle cells. This gives the aortic wall the tensile strength to withstand the pressure of blood pumped from the heart during systole, and the elasticity to expand and accommodate the left ventricular stroke volume and to, subsequently, recoil to its original diameter and push the blood forward for systemic perfusion. Aortic aneurysm involves structural degradation of the aortic wall and focal dilatation of the aortic lumen. It is a devastating health problem with no effective treatment. Current management strategies for AAA patients include antihypertensive drugs and surgical repair for severe cases of AAA which are not without limitations and complications. A number of proteases (matrix metalloproteinases, serine and cystein proteases), and their inhibitors (tissue inhibitor of metalloproteases and cystatin) have been shown to contribute to AAA development and progression. In this review we will summarize the published literature on the role of ECM-regulatory proteins, mainly proteases and their inhibitors, in aortic function and aneurysm formation, with a focus on abdominal aortic aneurysm.

Pathogenic mechanisms and the potential of drug therapies for aortic aneurysm

“…Metalloproteinases are a large family of enzymes that include MMPs, disintegrin metalloproteinases (ADAMs), and ADAMs with a thrombospondin domain (ADAM-TS). MMPs are believed to play a critical role in the degradation of aortic ECM and have also been suggested to have non-ECM functions, which directly contributes to aneurysm formation (15,122,140,171,221); ADAMTS are also extracellular metalloproteinases that can degrade various ECM proteins, particularly proteoglycans. ADAMs, on the other hand, are membrane-bound metalloproteinases that impose their action primarily through processing of membrane-bound cytokines and growth factors.…”

“…MMPs can be inhibited by tissue inhibitor of metalloproteinases (TIMPs). An overview of the physiology of MMPs and TIMPs in aortic aneurysm and their contribution to ECM and non-ECM events has been reviewed elsewhere (15,100).…”

Structurally abnormal collagen fibrils in abdominal aortic aneurysm resist platelet adhesion

“…A perturbation in the collagen fibril structure could thus impact platelet–collagen interaction and ensuing thrombus formation 8,9 . Vascular diseases such as abdominal aortic aneurysms (AAA) and atherosclerosis are characterized by significant, atypical remodeling of the vessel wall 10,11 and an imbalance in collagen synthesis and degradation 12,13 . However, little attention has been given to the thrombogenic potential of the remodeled, collagen‐rich vessel wall, which initiates the coagulation cascade by modulating platelet adhesion to collagen fibrils.…”