Topological determinants and consequences of adventitial responses to arterial wall injury

Arteries are composed of 3 concentric tissue layers which exhibit different structures and properties. Because arterial injury is generally initiated at the interface with circulating blood, most studies performed to unravel the mechanisms involved in injury-induced arterial responses have focused on the innermost layer (intima) rather than on the outermost adventitial layer. In the present review, we focus on the involvement of the adventitia in response to various types of arterial injury leading to vascular remodeling. Physiologically, soluble vascular mediators are centrifugally conveyed by mass transport toward the adventitia. Moreover, in pathological conditions, neomediators and antigens can be generated within the arterial wall, whose outward conveyance triggers different patterns of local adventitial response. Adventitial angiogenesis, immunoinflammation, and fibrosis sequentially interact and their net balance defines the participation of the adventitial response in arterial pathology. In the present review we discuss 4 pathological entities in which the adventitial response to arterial wall injury participates in arterial wall remodeling. Hence, the adventitial adaptive immune response predominates in chronic rejection. Inflammatory phagocytic cell recruitment and initiation of a shift from innate to adaptive immunity characterize the adventitial response to products of proteolysis in abdominal aortic aneurysm. Adventitial sprouting of neovessels, leading to intraplaque hemorrhages, predominates in atherothrombosis. Adventitial fibrosis characterizes the response to mechanical stress and is responsible for the constrictive remodeling of arterial segments and initiating interstitial fibrosis in perivascular tissues. These adventitial events, therefore, have an impact not only on the vessel wall biology but also on the surrounding tissue.     

Atherosclerosis--an immune disease: The Anitschkov Lecture 2007

Atherosclerosis is an inflammatory disease. This article reviews the emergence of this concept from studies of patients and their lesions, experimental animal models, and epidemiological cohorts. Immunohistochemical studies identified immune cells and mediators and provided evidence for inflammatory activation in the atherosclerotic lesion. In parallel, cell culture studies demonstrated the capacity of vascular cells to interact with immune cells. Subsequent studies of clinical and epidemiological materials have identified inflammatory markers and immunoregulatory genes as contributors of risk for myocardial infarction and stroke. Finally, experiments using gene-targeted mice have provided mechanistic understanding of the disease process. It is now thought that the atherosclerotic process is initiated when low-density lipoproteins accumulate in the intima, activate the endothelium, and promote recruitment of monocytes and T cells. Monocytes differentiate into macrophages, internalize modified lipoproteins, and end up as foam cells. T cells in lesions recognize local antigens and mount T helper-1 responses that contribute to local inflammation and plaque growth. This atherogenic pathway is counterbalanced by anti-inflammatory signals provided by regulatory immunity. Intensified inflammatory activation may lead to local proteolysis, plaque rupture, thrombus formation, ischemia and infarction. Novel therapeutic opportunities may emerge from understanding the role of inflammation in atherosclerosis.     

Inflammatory cytokines stimulate vascular smooth muscle cells locomotion and growth by enhancing alpha5beta1 integrin expression and function

The formation of atherosclerotic lesions requires the migration of vascular smooth muscle cells from the media into the intima of the artery and their proliferation. These events, which are preceded and accompanied by inflammation, are modulated by integrin receptors linking vascular smooth muscle cells to extracellular matrix molecules. Among them, fibronectin induces vascular smooth muscle cells to acquire the phenotype they show in the atherosclerotic plaque. Here we show that amounts of interleukin-1 beta, tumor necrosis factor alpha and interferon-gamma as possibly released by activated immune cells infiltrating atherosclerotic lesions, upregulate vascular smooth muscle cell expression of the alpha5beta1 integrin, a fibronectin receptor. This improves vascular smooth muscle cell capability of migrating toward soluble or anchored fibronectin and of adhering to immobilized fibronectin. The latter effect, in turn, augments vascular smooth muscle cell proliferative response to mitogens, as suggested by the increase of intracellular pH. Finally, the effects that inflammatory cytokines have on vascular smooth muscle cell locomotion and growth, are specifically blocked by anti-alpha5beta1 antibodies. As fibronectin and alpha5beta1 levels are augmented in vivo in the atherosclerotic plaques, these findings support the use of integrin antagonists as potential adjuvants in atherosclerosis treatment.     

The role of stem cells in atherosclerosis

Accumulating evidence indicates the involvement of stem cells and/or progenitors in the development of arteriosclerosis, including transplant arteriosclerosis, angioplasty-induced restenosis, vein graft atherosclerosis and spontaneous atherosclerosis. Recently, it was demonstrated that stem/progenitor cells existing in the circulation and adventitia contribute to endothelial repair and smooth muscle cell (SMC) accumulation. Atherosclerosis can be initiated by endothelial death in specific areas, e.g. bifurcation regions, and subsequent replacement by stem/progenitor cells. Meanwhile, progenitor cells from blood and the adventitia migrate into the intima where they proliferate and differentiate into neo-SMC. Stem/progenitor cells are responsible for the formation of atherosclerotic lesions, which appear as an inflammatory disease. Thus, these cells may be a source of endothelial cells and SMC, and might have implications for cellular, genetic, and tissue engineering approaches to vascular disease.     

The adventitia: a dynamic interface containing resident progenitor cells

Conventional views of the tunica adventitia as a poorly organized layer of vessel wall composed of fibroblasts, connective tissue, and perivascular nerves are undergoing revision. Recent studies suggest that the adventitia has properties of a stem/progenitor cell niche in the artery wall that may be poised to respond to arterial injury. It is also a major site of immune surveillance and inflammatory cell trafficking and harbors a dynamic microvasculature, the vasa vasorum, that maintains the medial layer and provides an important gateway for macrophage and leukocyte migration into the intima. In addition, the adventitia is in contact with tissue that surrounds the vessel and may actively participate in exchange of signals and cells between the vessel wall and the tissue in which it resides. This brief review highlights recent advances in our understanding of the adventitia and its resident progenitor cells and discusses progress toward an integrated view of adventitial function in vascular development, repair, and disease.     

茶多酚对兔颈总动脉血管成形术后再狭窄的影响

为探讨茶多酚对血管成形术后动脉中膜平滑肌增生及胶原增生的影响,以及与组织型纤溶酶原激活物和血管紧张素Ⅱ活性改变的关系,将雄性新西兰白兔30只随机分为对照组、低剂量茶多酚组和高剂量茶多酚组,用球囊导管剥脱右颈总动脉内皮,造成内皮及中膜损伤,分别在术前、术后3、7、11、14、22和28 d采动脉血应用酶联免疫法测血浆组织型纤溶酶原激活物活性及放射免疫法测血管紧张素Ⅱ血清水平,术后28 d处死动物并取右颈总动脉观察动脉中膜平滑肌和胶原增生程度.结果发现,高剂量茶多酚组组织型纤溶酶原激活物血浆活性为0.169±0.067 IU/L,低剂量茶多酚组为0.141±0.043 IU/L,对照组为0.126±0.043 IU/L,高剂量茶多酚组高于对照组和低剂量茶多酚组,差异具有显著性(P<0.05).高剂量茶多酚组血管紧张素Ⅱ血清水平为1 229±283 ng/L,低剂量茶多酚组为1 302±284 ng/L,对照组为1 309±263 ng/L,三组动物术后血管紧张素Ⅱ血清水平比较差异无显著性.高剂量茶多酚组动脉中膜胶原含量为50.1%+5.82%、低剂量茶多酚组为56.7%±2.3%,对照组为62.8%±2.1%,高剂量茶多酚组低于对照组及低剂量茶多酚组,差异具有显著性 (P<0.05);低剂量茶多酚组低于对照组,差异具有显著性(P<0.001).高剂量茶多酚组中膜平滑肌细胞计数为0.022±0.006/μm2,低剂量茶多酚组为0.034±0.008/μm2,对照组为0.033±0.007/μm2,高剂量茶多酚组低于对照组及低剂量茶多酚组,差异具有显著性(P<0.01).结果提示,高剂量茶多酚可提高血管成形术后血浆组织型纤溶酶原激活物活性,对血管紧张素Ⅱ血清水平无显著性影响,可抑制动脉中膜胶原及平滑肌细胞的增生,这可能有助于减轻或预防动脉血管成形术后再狭窄.     

外膜炎症诱发载脂蛋白E基因敲除鼠冠状动脉粥样硬化病灶

研究载脂蛋白E基因敲除(载脂蛋白E°)小鼠冠状动脉内粥样硬化病灶的分布、组成与动脉外膜炎症的关系.取载脂蛋白E°小鼠心脏作连续切片,Movat法染色,追踪冠状动脉主干及其心肌内的小分支;寻找病灶,观察病灶内组成,分析其分布规律.复制小鼠股动脉外膜无菌性炎症模型,用免疫组织化学方法检查内膜粘附分子的表达.结果发现,冠状动脉主干内有延伸病灶,在主干以下分支(包括心肌内小分支)内有在原位生成的病灶,在两类病灶相邻的外膜有炎性细胞浸润,外膜炎症面积大于动脉粥样硬化病灶累及的内膜面积,亦发现一些部位血管外有炎性细胞浸润,而尚无病灶形成.原位病灶均发生于心室壁,大的原位病灶多发生在左室壁心肌内、血管分支处和乳头肌附近的冠状动脉分支内.股动脉外膜炎症可诱发内膜表达细胞间粘附分子1和血管细胞粘附分子1,同时伴白细胞的附壁.以上提示血管外膜炎症是小鼠冠状动脉内病灶的一个始动环节.     

Blood flow-dependent arterial remodelling is facilitated by inflammation but directed by vascular tone

AIMS: Altered blood flow affects vascular tone, attracts inflammatory cells, and leads to microvascular remodelling. We tested the hypothesis that inflammation facilitates the remodelling response, but that vascular tone determines its direction (inward or outward). METHODS AND RESULTS: Mouse mesenteric resistance arteries were ligated to create either increased blood flow or low blood flow in vivo. In vivo microscopy was used to determine changes in vascular tone. Structural remodelling was studied after 2 days, with or without macrophage depletion. In order to characterize the inflammatory response, immunostaining, confocal microscopy, and real-time PCR were used. To address the role of vascular tone in remodelling, arteries were treated with the vasodilator amlodipine during organ culture. Vessels exposed to high blood flow dilated, whereas low flow induced constriction. After 1 day, inflammatory markers showed a complex but remarkably similar increase in expression during high flow and low flow. Both high-flow and low-flow vessels showed an increase in the number of adventitial macrophages. Depletion of macrophages eliminated flow-induced remodelling. Manipulation of vascular tone reversed inward remodelling in response to low blood flow. CONCLUSION: Altered blood flow triggers an inflammatory response that facilitates remodelling. Vascular tone is a crucial determinant of the direction of the remodelling response.     

Adventitial biology: differentiation and function

Recent evidence indicates that stem/progenitor cells are present in the adventitia and participate in vascular repair and the formation of neointimal lesions in severely damaged vessels. Data have also demonstrated that these resident stem/progenitor cells could differentiate into endothelial or smooth muscle cells in response to different stimuli. Under pathological conditions, adventitial inflammation results in releasing a panel of cytokines, such as stromal cell-derived factor-1 and tumor necrosis factor-α, that may lead to local stem/progenitor mobilization and differentiation. Overall, these data support the impact of the adventitial progenitors in pathophysiological processes of lesion development in the arterial wall. In the present review, we aim to summarize the data concerning the presence of the resident stem cells and discuss the pathological impact of the adventitia in vascular diseases. We will also discuss the possible signal pathways orchestrating stem cell differentiation toward vascular lineage and highlight controversial issues related to the role of adventitial progenitors.     

Negative regulation of inflammation by Fas ligand expression on the vascular endothelium

It is generally believed that the vascular endothelium serves as a barrier to inflammation by providing a nonadherent surface to leukocytes. Recently, we reported that vascular endothelial cells (ECs) express Fas ligand, which functions to actively inhibit inflammation by inducing apoptosis in Fas-bearing leukocytes. The inflammatory cytokine TNF alpha downregulates Fas ligand expression with an accompanying decrease in EC cytotoxicity toward Fas-bearing cells in co-culture. Endothelial Fas ligand expression in arteries is also downregulated by the local administration of TNF alpha, and this correlates with robust mononuclear cell infiltration of the subendothelial space. This TNF alpha-induced mononuclear cell infiltration is inhibited by pre-infecting the endothelium with a replication-defective adenovirus that constitutively expresses Fas ligand. Under these conditions, adherent leukocytes undergo apoptosis rather than extravasation. These findings suggest that Fas ligand expression on the vascular endothelium functions to inhibit inflammatory responses that are often associated with vascular disorders.     

Markers of hemostasis and systemic inflammation in heart disease and atherosclerosis in smokers

Smoking is a major cause of both chronic obstructive pulmonary disease (COPD) and coronary heart disease, the latter being more common in individuals with COPD. Acute coronary events are usually caused by the development of a platelet-rich thrombus associated with atheromatous plaque rupture or erosion. Levels of systemic biomarkers of inflammation and hemostasis may reflect the presence of atherosclerosis and predisposition to thrombosis, and may allow identification of "vulnerable plaque" and "vulnerable blood" in "vulnerable patients." Hemostasis and inflammation, often viewed as separate processes, are integrated closely, and their response to smoking likely has contributed to the current coronary heart disease epidemic. Coagulation is initiated after exposure of blood to tissue factor present in atheromatous plaques. Fibrinogen and other hemostatic factors important in thrombus formation are influenced by inflammatory stimuli, possibly reflecting both vascular and systemic inflammation. Smokers who develop COPD may have higher basal levels of inflammatory markers, such as fibrinogen, due to lung damage, and respiratory infections to which they are prone may further increase levels, predisposing smokers to coronary events. In summary, smoking predisposes to coronary heart disease and the mechanisms may involve proinflammatory and procoagulant changes. These changes may be more marked in smokers with COPD.     

Myofibroblast-mediated adventitial remodeling: an underestimated player in arterial pathology

The arterial adventitia has been long considered an essentially supportive tissue; however, more and more data suggest that it plays a major role in the modulation of the vascular tone by complex interactions with structures located within intima and media. The purpose of this review is to summarize these data and to describe the mechanisms involved in adventitia/media and adventitia/intima cross-talk. In response to a plethora of stimuli, the adventitia undergoes remodeling processes, resulting in positive (adaptive) remodeling, negative (constrictive) remodeling, or both. The differentiation of the adventitial fibroblast into myofibroblast (MF), a key player of wound healing and fibrosis development, is a hallmark of negative remodeling; this can lead to vessel stenosis and thus contribute to major cardiovascular diseases. The mechanisms of fibroblast-to-MF differentiation and the role of the MF in adventitial remodeling are highlighted herein.     

Lymphocytes and the adventitial immune response in atherosclerosis

Although much of the research on atherosclerosis has focused on the intimal accumulation of lipids and inflammatory cells, there is an increasing amount of interest in the role of the adventitia in coordinating the immune response in atherosclerosis. In this review of the contributions of the adventitia and adventitial lymphocytes to the development of atherosclerosis, we discuss recent research on the formation and structural nature of adventitial immune aggregates, potential mechanisms of crosstalk between the intima, media, and adventitia, specific contributions of B lymphocytes and T lymphocytes, and the role of the vasa vasorum and surrounding perivascular adipose tissue. Furthermore, we highlight techniques for the imaging of lymphocytes in the vasculature.     

Inflammation and atherosclerosis

Atherosclerosis is a vascular pathology in which inflammation plays a major role at every stage of the disease. The inflammatory process develops in response to abnormal cholesterol deposits in the intima of large arteries. The inflammatory reaction is initiated by a phase of endothelial activation induced by cytokines, oxidized low density lipoprotein (LDL) and/or changes in endothelial shear stress. This leads to the primary expression of endothelial adhesion molecules and chemokines followed by the recruitment and activation of circulating monocytes and lymphocytes. The clinical manifestations of atherosclerosis, including acute coronary syndromes, are the consequences of atherosclerotic plaque rupture/erosion that triggers thrombus formation leading to the occlusion of the vessel lumen. The local inflammatory process at the level of the atherosclerotic plaque might influence the stability of the plaque through its potential effects on the extracellular matrix, and on the plaque thrombogenicity. In humans, systemic inflammation has been recognized as a major risk factor of occurrence of acute coronary syndromes.     

The Roles of Neutrophils in Cytokine Storms

A cytokine storm is an abnormal discharge of soluble mediators following an inappropriate inflammatory response that leads to immunopathological events. Cytokine storms can occur after severe infections as well as in non-infectious situations where inflammatory cytokine responses are initiated, then exaggerated, but fail to return to homeostasis. Neutrophils, macrophages, mast cells, and natural killer cells are among the innate leukocytes that contribute to the pathogenesis of cytokine storms. Neutrophils participate as mediators of inflammation and have roles in promoting homeostatic conditions following pathological inflammation. This review highlights the advances in understanding the mechanisms governing neutrophilic inflammation against viral and bacterial pathogens, in cancers, and in autoimmune diseases, and how neutrophils could influence the development of cytokine storm syndromes. Evidence for the destructive potential of neutrophils in their capacity to contribute to the onset of cytokine storm syndromes is presented across a multitude of clinical scenarios. Further, a variety of potential therapeutic strategies that target neutrophils are discussed in the context of suppressing multiple inflammatory conditions.     

Anti-inflammatory mechanisms in the vascular wall

The role of vascular cells during inflammation is critical and is of particular importance in inflammatory diseases, including atherosclerosis, ischemia/reperfusion, and septic shock. Research in vascular biology has progressed remarkably in the last decade, resulting in a better understanding of the vascular cell responses to inflammatory stimuli. Most of the vascular inflammatory responses are mediated through the IkappaB/nuclear factor-kappaB system. Much recent work shows that vascular inflammation can be limited by anti-inflammatory counteregulatory mechanisms that maintain the integrity and homeostasis of the vascular wall. The anti-inflammatory mechanisms in the vascular wall involve anti-inflammatory external signals and intracellular mediators. The anti-inflammatory external signals include the anti-inflammatory cytokines, transforming growth factor-beta, interleukin-10 and interleukin-1 receptor antagonist, HDL, as well as some angiogenic and growth factors. Physiological laminar shear stress is of particular importance in protecting endothelial cells against inflammatory activation. Its effects are partly mediated through NO production. Finally, endogenous cytoprotective genes or nuclear receptors, such as the peroxisome proliferator-activated receptors, can be expressed by vascular cells in response to proinflammatory stimuli to limit the inflammatory process and the injury.     

血管成形术后血管外膜改变与血管重塑的相关性研究

目的:探讨大鼠胸主动脉血管成形术后血管外膜激活与血管重塑的相关性。方法:用6F人冠状动脉快速交换球囊损伤大鼠胸主动脉,术后2周和6周取材,行血管形态学定量分析,并行增殖细胞核抗原(PCNA)免疫组织化学染色,观察PCNA在血管外膜上的表达。结果:血管成形术组血管外膜细胞数量、血管外膜细胞增殖指数,外膜面积、厚度均较对照组显著增大(P<0.05),血管外弹力板围绕面积、内弹力板围绕面积和管腔面积较对照组显著减小(P<0.05),血管呈收缩性重塑。结论:血管成形术后,血管外膜被牵拉激活,导致外膜细胞分裂、增殖,以及血管收缩性重塑,参与再狭窄的发生。     

Extracardiac vascular and neural lesions in the toxic oil syndrome.

The toxic oil syndrome is a multisystemic disease caused by the ingestion of adulterated rapeseed oil. The basic lesion is a peculiar vasculitis that affects mainly the intima, showing the features of an endovasculitis. Vessels of every type and size are involved, affecting practically every organ. The vascular lesions begins with endothelial damage that varies from cellular swelling to cellular necrosis. It then progresses by mixed cellular inflammatory infiltration of the intima and, in some cases, of the media and adventitia. In some cases the infiltrate is rich in eosinophils and a few show foamy histiocytes. Proliferation of myointimal cells and in advanced stages fibroblastic proliferation causes narrowing or obliteration of the vascular lumen. Thromboembolic complications perpetuate the vascular lesion and compound the ischemia and parenchymal atrophy of several organs. The peripheral nerve lesions begin with an inflammatory neuropathy with lymphocytic perineuritis and progress to perineural fibrosis with secondary axonal degeneration. Skeletal muscle lesions exhibit an interstitial inflammatory myopathy at first, followed by a neurogenic muscular atrophy. A direct effect of unidentified toxic substances, possibly free radicals, may cause the endothelial lesion. Other factors, such as immunopathologic mechanisms of delayed hypersensitivity, may contribute to the progression of the vascular lesions.     

Localisation of mRNA for JE/MCP-1 and its receptor CCR2 in atherosclerotic lesions of the ApoE knockout mouse

MCP-1 has potent chemotactic activity for monocytes and is strongly implicated in the pathogenesis of atherosclerosis. In the present study, we have used in situ hybridisation to examine the gene expression of JE, the murine homologue of MCP-1, and its receptor, CCR2, during the development of atherosclerotic lesions in the ApoE knockout mouse. Interestingly, the earliest expression of JE detected during lesion development was found to be localised in mesenchymal cells in the adventitia and not in the intima. Macrophages were subsequently found to accumulate in these affected regions of the adventitia and these cells were found to express high levels of JE. At this stage, early macrophage-rich lesions with high expression of JE were also seen in the intima, but expression of mRNA for the receptor for JE (CCR2) was only found on adventitial macrophages and not in the intima. This sequence of events suggests that adventitial inflammation may be an important early event in lesion development and responsible for the subsequent accumulation of macrophages in the intima possibly by recruitment from the adventitia as well as via the vessel lumen.