Time-Dependent Pathological Changes in Hypoperfusion-Induced Abdominal Aortic Aneurysm

Abstract

Hypoperfusion due to vasa vasorum stenosis can cause wall hypoxia and abdominal aortic aneurysm (AAA) development. Even though hypoperfusion is an important contributor toward pathological changes in AAA, the correlation between hypoperfusion and AAA is not fully understood. In this study, a time-dependent semi-quantitative pathological analysis of hypoperfusion-induced aortic wall changes was performed to understand the mechanisms underlying the gradual degradation of the aortic wall leading to AAA formation. AAA-related factors evaluated in this study were grouped according to the timing of dynamic change, and five groups were formed as follows: first group: angiotensin II type 1 receptor, endothelin-1 (ET-1), and malondialdehyde (MDA); second group: matrix metalloproteinase (MMP)-2, -9, -12, M1 macrophages (Mac387+ cells), and monocyte chemotactic protein-1; third group: synthetic smooth muscle cells (SMCs); fourth group: neutrophil elastase, contractile SMCs, and angiotensinogen; and the fifth group: M2 macrophages (CD163+ cells). Hypoxia-inducible factor-1α, ET-1, MDA, and MMP-9 were colocalized with alpha-smooth muscle actin cells in 3 h, suggesting that hypoperfusion-induced hypoxia directly affects the activities of contractile SMCs in the initial stage of AAA. Time-dependent pathological analysis clarified the cascade of AAA-related factors. These findings provide clues for understanding complicated multistage pathologies in AAA.

On vasa vasorum: A history of advances in understanding the vessels of vessels

“…Vasa vasorum expansion in human AAA was found in abundance within the adventitia and outer media, although this was not observed in the associated ILTs ( 152 ). Further support for the theory that hypoperfusion of vasa vasorum invokes and exacerbates progression of AAA comes from work in a rat model ( 153 – 156 ). Removal of perivascular tissue, insertion of a polyurethane catheter in the infrarenal abdominal aorta, and suture ligation of the aorta over the catheter together resulted in hypoperfusion of the adventitial vasa vasorum without disrupting blood flow in the aortic lumen and led to a twofold expansion of the aortic diameter within 14 days ( 155 ).…”

“…A follow-up study using the same hypoperfusion technique in rats noted diffuse and hyperlocal HIF-1α expression in the aortic wall within 24 hours of hypoperfusion onset with elastin fragmentation, increased gelatinase activity, decreased collagen content, and apoptotic SMCs observed after 28 days ( 153 ). Most recently, the same group reported rapid detection of HIF-1α in medial SMCs and macrophages (within 3 hours after ligation) and, despite an increased number of vasa vasorum, inferred that their hypoperfusion exerts time-dependent effects on aortic wall biology including potential hypoxia-mediated changes in contractile SMCs before onset of AAA ( 156 ). Pretreatment with a phosphodiesterase inhibitor (K-134) was shown to prevent aortic rupture in the hypoperfusion rat model, with noted decreases in vasa vasorum stenosis and medial hypoxia as well as prevention of rupture in elastase- and Ang-II–induced models of AAA ( 157 ).…”

Mechanisms of abdominal aortic aneurysm progression: A review

“…35,48 Since the abnormal hemodynamic pattern is unlikely to be established before aortic dilation, it is reasonable to assume that the aortic wall hypoxia might be the major trigger of MCP-1 in PVAT, which is in line with Kugo’s study that hypoxia affected the contraction of VSMC function and activity and may be a possible inducer of the phenotypic transformation of VSMCs in the early stage of AAA. 54 In other words, the VV stenosis might be prior to the VSMC phenotypic transformation and AAA formation. What is more, the hypoxia-induced AAA model expanded significantly within only 14 days after modeling and the sac rupture occurrence reached 20% within 28 days, 52,53 suggesting that adventitial VV hypoperfusion and sac wall hypoxia are more likely to be the crucial mechanisms of terminal AAAs.…”

Toward a unified pathophysiology in COVID-19 acute aortopathies

“…In medium and large arteries, this pathology involves the external VV as well, while the internal VV, because of their small caliber, thinner walls, and lower blood inflow, disappear as a direct result of the antecedent endothelial damage ( Fig , B ). 5 As shown, 6 the subsequent hypoxia in arterial walls produces hypoxia-inducible factor 1a, in turn releasing other substances, such as matrix metalloproteinases, macrophages, monocytes, and chemoattractant proteins, specific for secondary degenerative-inflammatory lesions. In addition to endothelin-1 and angiotensin II type 1, vasoconstrictors are active on the VV as well.…”

“…In addition to endothelin-1 and angiotensin II type 1, vasoconstrictors are active on the VV as well. 6 This process worsens the local preinflammatory or inflammatory conditions, already promoted by preexisting endothelial dysfunction, increases the degradation of collagen and elastic fibers, and greatly decreases the population of smooth muscle bundles in the media layer. In the VV, we have to consider, as an additional functional factor hampering blood inflow, their radial or circumferential external compression by inelastic atherosclerotic vessels, mainly when stressed by arterial hypertension.…”