Novel aspects of the pathogenesis of aneurysms of the abdominal aorta in humans

Abstract

Aneurysm of the abdominal aorta (AAA) is a particular, specifically localized form of atherothrombosis, providing a unique human model of this disease. The pathogenesis of AAA is characterized by a breakdown of the extracellular matrix due to an excessive proteolytic activity, leading to potential arterial wall rupture. The roles of matrix metalloproteinases and plasmin generation in progression of AAA have been demonstrated both in animal models and in clinical studies. In the present review, we highlight recent studies addressing the role of the haemoglobin-rich, intraluminal thrombus and the adventitial response in the development of human AAA. The intraluminal thrombus exerts its pathogenic effect through platelet activation, fibrin formation, binding of plasminogen and its activators, and trapping of erythrocytes and neutrophils, leading to oxidative and proteolytic injury of the arterial wall. These events occur mainly at the intraluminal thrombus-circulating blood interface, and pathological mediators are conveyed outwards, where they promote matrix degradation of the arterial wall. In response, neo-angiogenesis, phagocytosis by mononuclear cells, and a shift from innate to adaptive immunity in the adventitia are observed. Abdominal aortic aneurysm thus represents an accessible spatiotemporal model of human atherothrombotic progression towards clinical events, the study of which should allow further understanding of its pathogenesis and the translation of pathogenic biological activities into diagnostic and therapeutic applications.

Figure 1

Biological features of the intraluminal thrombus (ILT). (A) Macroscopic view showing the red, most recent, luminal layer of the ILT and the abluminal proteolysed layer. (B) Microscopic aspect of the luminal layer including trapped red blood cells and a large area of nucleated, cell-rich fibrin (haematoxylin and eosin, ×4). (C) Immunostaining of platelet glycoprotein Ib on the luminal ILT surface (×4). (D) Immunostaining of neutrophils (CD66b) on the luminal surface (×4).

Figure 2

Biological features of the outer media and adventitia in human aneurysm of the abdominal aorta (AAA). (A) General view of the outer part of an AAA showing the inner ILT, the remaining media (difficult to delimit exactly in the absence of elastic laminae), and the highly vascularized outer adventitia, containing well-organized inflammatory granuloma (haematoxylin and eosin, ×4). (B) Cholesterol crystal clefts in the outer media (haematoxylin and eosin, ×10). (C) Granuloma can be easily identified as adventitial tertiary lymphoid organs by their high density of B lymphocytes (CD 20 immunostaining, ×4). (D) Presence of a high density of phagocytosed haemosiderin mainly in the outer part of the media (Perls blue staining, ×4), providing evidence of convection towards the adventitia of haem released by the ILT.

Figure 3

Schematic representation of the impact of the blood–ILT interface on medial degradation and the adventitial inflammatory, angiogenic and fibrotic responses in human AAA. Abbreviations: ATLO, adventitial tertiary lymphoid organ; and RBCs, red blood cells.