The pathology of Kawasaki disease aortitis: a study of 37 cases.

BACKGROUND: Kawasaki disease (KD) is a systemic vasculitis syndrome that occurs most frequently in children. Most clinical and pathological studies have focused on its coronary artery lesions. To date, no detailed studies of the aorta have been conducted. We studied KD autopsy cases with the aims of clarifying the time-course of changes in aortic lesions, the differences in the inflammatory cells and degree of inflammation at various aortic sites, and the progression of the inflammation. MATERIALS AND METHODS: The study materials were aortic specimens taken from 37 KD autopsy cases (acute phase: 19; remote phase: 18). Twenty-seven of the cases also had coronary aneurysms. We chose 3 aortic sites, i.e., the thoracic aorta, aortic root and aortic bifurcation, and we histologically observed and compared those sites in regard to the changes with time, the kinds of infiltrating cells and the number of inflammatory cells. We also observed the relationship between the vasa vasorum and inflammatory cell localization in the tunica media, and examined the progression of inflammation in the tunica media. RESULTS: Destruction of the vascular architecture was not seen in any of the 37 cases, but inflammatory cell infiltration was observed in 90% of the acute-phase cases. The inflammatory cell infiltration involved the tunica intima and tunica adventitia of the aorta on the 6th disease-day, and all layers of the aorta on the 13th disease-day; the infiltration peaked on the 18th disease-day. The infiltration gradually disappeared thereafter, and no significant infiltration was seen in the remote phase. The infiltrating inflammatory cells consisted mainly of CD163-positive macrophages. Comparison of the 3 sites of the aorta showed that the inflammatory cell infiltration was more severe in the aortic root and aortic bifurcation than in the thoracic aorta. The progression of inflammation to the aortic tunica media from the adventitia showed 2 patterns: 1 in which macrophages were aggregated around the vasa vasorum; and a second in which there was no such aggregation around the vasa vasorum, but there was diffuse inflammatory cell infiltration of the tunica media. In addition to this, there were findings of direct infiltration of cells from the tunica intima into the tunica media. CONCLUSION: Inflammation in KD occurs in the aorta. The changes with time and the kinds of infiltrating cells were the same as reported to date for coronary arteries in KD. There were differences in the degree of inflammation among the 3 aortic sites. It can be thought that the inflammation from the adventitia to the media progresses via the vas vasorum, and also, there is a possibility of spreading directly. From the intima to the media, inflammation spreads directly. However, formation of aneurysms and destruction of the vascular architecture of the aorta were absent in this study, unlike in coronary arteries.

Immune cells and vasa vasorum in the tunica media of atherosclerotic coronary arteries.

In coronary artery disease (CAD), the disruption of the tunica media immune privilege manifests as increased leukocyte infiltration and the formation of vasa vasorum. We aimed to characterize the immune privilege status of the tunica media in human coronary arteries (CAs) with atherosclerotic plaques, by comparing the abundance and composition of immune-cell infiltrates within the individual arterial-wall layers, and by evaluating vasa vasorum neovascularization of the tunica media. The tissue samples were obtained from 36 symptomatic patients with diffuse CAD (aged 60-72 years) who underwent coronary endarterectomy. T and B cells, macrophages and endothelial cells in the CAs were detected by immunohistochemistry. Morphological analysis of CAs showed significant atherosclerotic changes in all specimens. In the media, we observed damage and loss of smooth muscle cells, destruction of the extracellular matrix architecture, and fibrosis. There were 43.3% of immune cells in the intima, 50% in the adventitia, and 6.7% in the media. In the media, 51.1% of the immune cells were T cells (p ˂ 0.001 compared to B cells and macrophages; ANOVA, Scheffe post hoc analysis), 23.5% were B cells, and 25.4% were macrophages. The number of vasa vasorum in the media was 1 in 38.9% of CAs, 2-3 in 36.1%, and ≥4 in 25% of CAs. Our results indicate that, in atherosclerotic CAs, the immune privilege of the media is disrupted by the infiltration of T and B cells, macrophages, and the presence of vasa vasorum.

Hypoperfusion of the Aortic Wall Secondary to Degeneration of Adventitial Vasa Vasorum Causes Abdominal Aortic Aneurysms.

BACKGROUND: An abdominal aortic aneurysm (AAA), which affects approximately 10% of Japanese men aged ≥ 65 years, is frequently associated with hypertension, dyslipidemia, and other lifestyle- related diseases. The development of an AAA is attributed to chronic inflammation concomitant with arteriosclerotic changes. However, an accurate pathomechanism associated with AAA remains uncertain, and questions such as why only a particular group/percentage of patients with arteriosclerosis develop aneurysms and how diabetes suppresses aneurysm development remain unanswered. OBJECTIVE: We examined a novel mechanism to develop AAA based on histopathological findings following analysis of the human AAA tissues. Additionally, based on these findings, we developed a new animal model of AAA, in which the histopathological characteristics are similar to human AAA tissue. RESULTS: Recently, we identified stenosis of the vasa vasorum (VV) in aortic segments showing dilatation. The aorta is the largest artery in our circulatory system. Under physiological conditions, the inner layer of the aorta is nourished via direct diffusion of nutrients from the luminal blood flow, whereas the outer adventitia is primarily perfused by the VV. Therefore, hypoperfusion of the VV induces hypoxia and subsequent inflammation and tissue degeneration of the aortic wall, resulting in aneurysm formation. Based on these findings, we established an AAA animal model by reducing the blood flow through the VV to the aortic wall. AAA was successfully reproduced in our animal model. Histopathological findings in this model were indistinguishable from those observed in humans, and pronounced abnormality in lipid composition in blood vessel adventitia was also observed. CONCLUSION: Thus, hypoperfusion of the aortic wall appeared to be sufficient to cause inflammationinduced AAA. These findings may provide potential targets for novel therapeutics for the management of an AAA.

Vasoprotective effect of vitamin E: rescue of ethanol-induced atherosclerosis and inflammatory stress in rat vascular wall.

Chronic ethanol consumption increases the incidence of cardiovascular disease. The mechanisms underlying ethanol-induced susceptibility to cardiovascular disease continue to be defined. This study examines the hypothesis that chronic ethanol consumption plausibly induces vascular wall abnormalities via inflammatory reactions. In addition, it intends to find out whether vitamin E inhibits the abnormalities induced by ethanol in rats' vascular wall. Twenty four male Wistar rats were divided into three groups (n=8): Control ©, ethanol (E), and vitamin E treated ethanol (VETE) group. After 6weeks, the aortic and coronary wall changes, vascular endothelial growth factor (VEGF), alpha-1 glycoprotein and haptoglobin amounts in plasma, C-reactive protein levels(CRP), as well as the amount of aortic IL-6 were evaluated. The results revealed the elevation of polymorphonuclear (PMN) leukocyte in the vascular wall, disorganization of endothelium with ballooning of cells, proliferation of vasa-vasorum with an increase in the IL-6, CRP, as well as a decrease in VEGF and an increase in alpha-1 glycoprotein and haptoglobin in the ethanol group compared to the control group. Significant amelioration of aortic and coronary wall changes, along with the restoration of elevated level of IL6, CRP, and the decreased level of VEGF compared to that of the controls were found in vitamin E-treated animals. These findings strongly support the idea that heavy and chronic ethanol consumption initiates atherosclerosis by inflammatory stress, and that these effects can be alleviated by vitamin E as an anti-inflammatory agent.

Plaque-associated vasa vasorum in aged apolipoprotein E-deficient mice exhibit proatherogenic functional features in vivo.

OBJECTIVE: Neovascularization of human atherosclerotic plaques is implicated in plaque progression and destabilization, although its functional implications are yet unresolved. Here, we aimed to elucidate functional and morphological properties of plaque microvessels in mice in vivo. METHODS AND RESULTS: Atherosclerotic carotid arteries from aged (>40 weeks) apolipoprotein E-deficient mice were imaged in vivo using multiphoton laser scanning microscopy. Two distinct groups of vasa vasorum microvessels were observed at sites of atherosclerosis development (median diameters of 18.5 and 5.9 µm, respectively), whereas microvessels within the plaque could only rarely be found. In vivo imaging showed ongoing angiogenic activity and injection of fluorescein isothiocyanate-dextran confirmed active perfusion. Plaque vasa vasorum showed increased microvascular leakage, combined with a loss of endothelial glycocalyx. Mean blood flow velocity in plaque-associated vasa vasorum was reduced by ±50% compared with diameter-matched control capillaries, whereas mean blood flow was reduced 8-fold. Leukocyte adhesion and extravasation were increased 6-fold in vasa vasorum versus control capillaries. CONCLUSIONS: Using a novel in vivo functional imaging strategy, we showed that plaque-associated vasa vasorum were angiogenically active and, albeit poorly, perfused. Moreover, plaque-associated vasa vasorum showed increased permeability, reduced blood flow, and increased leukocyte adhesion and extravasation (ie, characteristics that could contribute to plaque progression and destabilization).

Vasa vasorum hypoxia: initiation of atherosclerosis.

We propose a new hypothesis pointing of a functional hypoxia in vasa vasorum, which might explain the initiation and the early development of the atherosclerosis in the deep layer of intima. Since vasa vasorum are end arteries, they easily develop hypoxia and/or ischemia in the cells of intima or media of arterial wall. The most vulnerable sites for hypoxia are the arterial bifurcations due to the anatomical and physiological reasons. They are also known to be the most common sites of atherosclerosis. The known risk factors for atherosclerosis, high blood pressure and nicotine, reduce the blood flow in the end branches of the vasa vasorum. The local ischemia will affect the endothelial cell structure and causes a local inflammation, which, in turn, makes it permeable to large particles such as microbes and LDL-lipoproteins and other fatty acids, which are phagocytozed by macrophages transforming them into foam cells. The present hypothesis explains most problems of the previous theories and offers a logical sequence of the events involved in the development of atherosclerosis.

CD154 and its receptors in inflammatory vascular pathologies.

CD154, a member of the tumor necrosis factor-alpha family, has recently been implicated in the pathophysiology of vascular diseases. Indeed, blockade of CD154 by neutralizing antibodies or genetic disruption in mice prevents atherosclerosis and atherothrombosis. CD154 is believed to interact mainly via the CD40 receptor, however, it has also been found to bind with alphaIIbbeta3 integrin and so induces platelet activation. Moreover, we (and others) have recently identified the integrins alpha5beta1 and Mac-1 as novel CD154 receptors expressed on many cell types. Here, we illustrate the various functional features of these molecules, while describing the increasingly important role of CD40 in CD154-associated vascular pathologies such as atherosclerosis and atherothrombosis.

The dynamic vasa vasorum.

The function of vasa vasorum is both to deliver nutrients and oxygen to arterial and venous walls and to remove "waste" products, either produced by cells in the wall or introduced by diffusional transport through the endothelium of the artery or vein. Although the relationship between changes in vasa vasorum characteristics and the development of atheromatous plaques is well documented, the role of vasa vasorum, especially in terms of their appearance and disappearance in disease processes such as atherosclerosis, are still not clearly understood in terms of their being causative or merely reactive. However, even if their proliferation is merely reactive, these new microvessels may be a source of disease progression by virtue of endothelial impairment and as a pathway for monocytic cells to migrate to sites of early disease. As both these features are aspects of the vasa vasorum function, this Review focuses on the following issues: 1) acute modulation of vasa vasorum patency due to surrounding compressive forces within vessel wall and due to variable tone in the smooth muscle within proximal vasa vasorum and 2) chronic angiogenic responses due to local cytokine accumulations such as occur in the wall of arteries in the presence of hypertension, hypercholesterolemia, accumulation of lipids, extravasated blood products (e.g., red blood cells, macrophages, inflammatory products) which attract monocytes, and response of vasa vasorum to pharmacological stimuli.

Neutrophil and endothelial cell activation in the vasa vasorum in vasculo-Behçet disease.

AIM: The aim of this study was to analyse the immunopathological mechanisms of vasculo-Behçet disease, which were also compared to cases of Takayasu's arteritis and inflammatory aneurysm to evaluate differences in inflammatory mechanisms. METHOD AND RESULTS: We reviewed six cases of vasculo-Behçet disease, four of Takayasu's arteritis and seven inflammatory aneurysms which underwent surgical repair. Immunohistochemical studies were performed on paraffin-embedded tissue using a labelled streptavidin-biotin method, as was in-situ hybridization for Epstein-Barr virus. Microscopically, neutrophils and lymphocytes accumulated around the vasa vasorum. Neutrophils were prominent as compared to Takayasu's arteritis and inflammatory aneurysm. Elastic fibres were not severely destroyed. Endothelial cells (ECs) of most vasa vasorum expressed HLA-DR. The number of vasa vasorum around which inflammatory infiltrating cells were observed in vasculo-Behçet disease was significantly greater than in inflammatory aneurysms and Takayasu's arteritis (P < 0.001). The cytokines IL-1alpha, TNF-beta and IFN-gamma were expressed in neutrophils and lymphocytes which were distributed around vasa vasorum, as well as neutrophils adherent to HLA-DR positive ECs. CONCLUSION: Our results suggest that vasculo-Behçet disease should be classified as a neutrophilic vasculitis targeting the vasa vasorum. Aneurysm formation may be related to degeneration of arterial wall caused by inflammation of the vasa vasorum.

Aetiopathogenesis of Takayasu's arteritis and BCG vaccination: the missing link?

Takayasu's arteritis is an inflammatory disease of unknown aetiology involving the aorta, its major branches and pulmonary arteries. Historical, epidemiological and immunological data are presented which suggest that BCG vaccination in the susceptible host might be important in the pathogenesis of Takayasu's arteritis. This hypothesis best explains the various known facts about the disease.