糖萼的内皮保护作用与动脉粥样硬化

血管内皮功能障碍在动脉粥样硬化的发病机制中担当着重要角色.作为血管内皮的保护性屏障,糖萼起着调控血管通透性,介导血流剪切力诱导的一氧化氮释放,抑制白细胞、血小板与内皮细胞的粘附及抗凝等一系列作用.本文主要就糖萼的完整性及其内皮保护的重要意义,以及其与动脉粥样硬化的密切关系作一综述.     

基质金属蛋白酶在动脉粥样硬化中的作用研究进展

动脉粥样硬化是引起冠状动脉粥样硬化性心脏病的众多因素中最重要的一种,严重威胁到人类的健康和生命。其发生源于各种原因导致的内皮细胞损伤,血管内皮的屏障功能遭受破坏,血液中的单核巨噬细胞、脂质、淋巴细胞及中性多形核白细胞广泛入侵到被剥脱的内皮下组织,发展为粥样斑块,引起血管重构,进一步导致斑块破裂,出血,继发血栓形成等。本文着重从几方面机制阐述基质金属蛋白酶削弱血管内皮细胞屏障功能,促进中层血管平滑肌细胞迁移和增殖,加重血管的结构改变,进一步促进循环炎性细胞浸润,斑块破裂,从而促进动脉粥样硬化疾病的发生、发展。     

血脂异常导致血管内皮细胞的氧化损伤

在正常生理情况下，血管内皮结构完整、功能正常，一方面通过屏障作用阻止低密度脂蛋白（low density lipoprotein，LDL）等大分子物质和单核细胞等血液细胞成分进入动脉内膜，另一方面又通过产生前列腺素（PCI2）等活性因子发挥抗凝、抑制平滑肌细胞增殖等多种功能。血液中大量LDL在内皮下的沉积导致内皮细胞损伤、单核细胞浸润、血小板粘附聚集、刺激血管平滑肌细胞向血管内膜迁移与增殖，巨噬细胞吞噬脂质而形成泡沫细胞，逐渐发展成动脉粥样硬化斑块。因此，保护内皮细胞免受损伤是防治动脉粥样硬化发生发展的关键。     

血管内皮功能障碍与冠状动脉疾病的关系及防治进展

血管内皮作为循环血液与血管平滑肌之间的中介组织，不仅仅是一层半透性屏障，而且还具有多种重要的生理功能，内皮细胞分泌多种血管活性物质，对维持血管壁张力、血液的流动、管壁的炎症修复和血管的增生具有重要的作用，是功能活跃的代谢组织。内皮细胞损伤会引起内皮功能障碍，与高血压、动脉粥样硬化、心力衰竭等心血管疾病的发生、发展有密切关系。本文就血管内皮功能、血管内皮细胞功能障碍与冠状动脉（冠脉）疾病的关系以及内皮功能保护措施做一综述。     

内皮细胞与动脉粥样硬化

从1865年His提出内皮的概念，到1980年Furehgou等揭示内皮依赖性血管舒张活动的现象这段漫长时间，血管内皮仅被认为是血液与血管壁之间的一个物理屏障。随着对内皮细胞研究的深入，其功能逐渐为大家所认识。目前认为内皮细胞是一个多功能器官，不仅具有屏障作用，还能作为多个配体的靶器官，并且能分泌多种因子，在血液流动、血管紧张度、白细胞和血小板黏附和平滑肌增殖中起重要作用。动脉粥样硬化发生是一个多层次的、各种因素和细胞成分相互影响的瀑布式发展过程，内皮细胞损伤是动脉粥样硬化的第一步，也是动脉粥样硬化形成的决定性因素。     

提高血流剪切应力调控动脉粥样硬化相关基因表达

血流剪切应力是造成动脉粥样硬化病变非随机灶性分布的主要因素。许多研究显示血流剪切应力通过调控内皮细胞的基因表型影响血管内皮的结构与功能,从而影响动脉粥样硬化病变的发生发展。增强型体外反搏驱动血液形成双脉冲灌注于全身,明显提高脉动剪切应力,长期使用可保护血管内皮,调控动脉粥样硬化相关基因的表达,有助于预防及治疗动脉粥样硬化。     

内皮细胞损伤与心肌无复流现象

内皮系统是一个动态的平衡系统,对于维持局部内环境的稳定十分重要.已经证实内皮细胞结构完整及功能正常对血管壁通透性屏障、免疫防御、抗凝、抗血栓及炎性反应均有重要作用.血管内皮细胞损伤与心肌无复流密切相关,可显著降低急性心肌梗死病人的生存率,防治血管内皮细胞损伤是临床工作的重要难题.研究显示:心肌缺血-再灌注易导致内皮细胞结构及功能损伤,促进无复流的发生发展;相应的临床干预措施在一定程度上可修复损伤内皮细胞,改善心肌无复流.本文主要针对缺血-再灌注时内皮细胞损伤的最新发生机制及临床处理做一综述,以期为防治心肌无复流提供理论依据.     

血管内皮功能失调的评价与治疗

血管内皮细胞不仅是血液与血管平滑肌之间的生理屏障，而且是高度活跃的代谢库，能合成多种血管活性物质，对维持正常的血液循环有重要的生理意义。内皮细胞发生改变可导致内皮功能失调。血管内皮功能失调参与多种心血管疾病的发生发展，逆转失调的内皮功能是心血管疾病防治的新趋势。本文着重综述了正常的血管内皮功能、内皮细胞功能失调的发生机制、内皮功能失调的临床评价方法及血管内皮功能失调的治疗方面的内容。     

血管内皮功能障碍与动脉粥样硬化

血管内皮不仅是血液与内皮下组织的屏障,还具有内分泌功能.当血管内皮功能障碍时,会引起一系列的病理生理反应,导致动脉粥样硬化.在内皮功能障碍向动脉粥样硬化演变的过程中,血管紧张素Ⅱ和氧化型低密度脂蛋白起重要作用.内皮细胞损伤时,机体自身的修复机制发挥作用,相关药物可改善内皮功能,稳定动脉粥样硬化,改善预后.内皮细胞功能的...     

活血化瘀药对血管内皮功能的影响

目前人们已经开始认识到血管内皮细胞（VECs）不仅是血液和血管平滑肌的屏障，而且是高度活跃的代谢库，参与凝血及抗血栓形成，调节血管张力，影响血管通透性。目前许多学者发现血瘀证与血管内皮损伤有着密切联系，并开始利用活血化瘀药调节血管内皮细胞的内环境及其分泌功能，从而逆转内皮功能，已成为一个新的研究方向。现对近年来活血化瘀药对血管内皮功能的影响综述如下。     

Endothelial dysfunction and arterial hypertension

The endothelium lines all blood vessels in the human body, it is the basic structure which ensures the action of substances circulating in the blood stream on the vascular wall. It is an organ the sound state of which is essential for the physiological function of the vascular system. Its impaired function is a basic factor in the genesis and development of vascular disease. Under physiological conditions the endothelium has antiadhesive and antithrombotic properties, it produces vasoactive substances, prevents the penetration of circulating substances and formed elements across the vascular wall, and via adhesion molecules it participates in the interaction with cells in the circulation. Risk factors of cardiovascular diseases such as hypertension, hyperlipidaemia, hyperglycaemia, smoking damage the function of endothelial cells and cause the development of endothelial dysfunction. In patients with arterial hypertension endothelial dysfunction is characterized by an impaired endothelium dependent relaxation, increased adhesion and permeability of endothelial cells, structural changes of the vascular wall. When the endothelium is damaged by released cytokines an increased expression of adhesion molecules occurs, adhesion and migration of inflammatory cells across the vascular wall. Cytoadhesion molecules are released from the surface of the endothelium into the circulation where the rise of their plasma levels can serve as a marker of endothelial damage. Endothelial dysfunction in hypertonic subjects contributes in a significant way to the development and progression of chronic vascular disease--atherosclerosis. Improvement of the damaged endothelial function is therefore at present a desirable therapeutic objective in the treatment of hypertension.     

Introduction to endothelial cell biology

Vascular endothelial cells form a monocellular layer on blood vessel walls with an estimated mass of 1.5 kg. One of the roles of endothelial cells is to control the hemodynamics through various metabolic activities affecting homeostasis, vascular tonus, blood fluidity, coagulating properties and blood cell adhesion. In other respects thousands of studies have underlined the crucial role of local blood flow conditions on their properties. However, the hemodynamic forces are different according to the anatomical site and to the type of blood vessels (arteries, veins, venules, ...). In microcirculation, the endothelial cells in the venules are particularly active and constitute the physiological site of liquid exchange (permeability) and above all cellular transit. During critical ischemia, the post-capillary venules are deeply involved. In other respects the properties of endothelial cells may be impaired in many diseases as atherosclerosis, hypertension, inflammation and metabolic diseases.     

Placental trophoblast-derived factors diminish endothelial barrier function

Although increased vascular permeability is an important event in the pathogenesis of preeclampsia, the origin of the circulating factor(s) that elicits this endothelial barrier dysfunction is not known. In this study, we use coculture of endothelial cells and placental trophoblast cells to determine whether placental trophoblasts are a potential source of the factor(s) that mediate the increased vascular permeability of preeclampsia. Human umbilical vein endothelial cells grown in Transwell inserts or on coverslips were cocultured with trophoblast cells isolated from normal and preeclamptic placentas or placenta conditioned media. Endothelial cell barrier function was determined by: 1). measurements of electrical resistance and leakage of horseradish peroxidase, and 2). immunofluorescent staining of vascular endothelial-cadherin, pan-cadherin, and occludin. Uterine myometrium endothelial cells were also studied for comparison. We observed the following: 1). electrical resistance was significantly (P < 0.01) decreased (compared with control endothelial cells) in endothelial cell monolayers cocultured with normal trophoblast cells and further reduced in endothelial cells cocultured with preeclamptic trophoblast cells; 2). an increased horseradish peroxidase leakage that was correlated with the decreased electrical resistance in cocultured cells; and 3). disorganized tight junction proteins and an altered distribution of vascular endothelial-cadherin and occludin in monolayers of endothelial cells cocultured with preeclamptic trophoblast cells. Similar responses were noted in uterine myometrium endothelial cells. We conclude that: 1). placental trophoblast cells produce factors that diminish the barrier function of endothelial cells; 2). endothelial tight junctions are more susceptible to factors released from preeclamptic trophoblast cells than from normal trophoblast cells; and 3). these results implicate trophoblast-derived factors in the increased vascular permeability associated with preeclampsia.     

Endothelial cells, fibroblasts and vasculitis

One of the most important questions in vasculitis research is not why inflammation of blood vessels occurs but why it persists, often in a site-specific manner. In this review we illustrate how stromal cells, such as fibroblasts and pericytes, might play an important role in regulating the site at which vasculitis occurs. Smooth muscle cells and fibroblasts directly influence the behaviour of overlying vascular cells, amplifying the response of the endothelium to proinflammatory agents such as TNF-alpha and allowing enhanced and inappropriate leucocyte recruitment. An abnormal local vascular stromal environment can therefore influence local endothelial function and drive the persistence of local vascular inflammation. However, such local vascular inflammation can have distant effects on the systemic vascular system, leading to widespread endothelial cell dysfunction. Vascular endothelial dysfunction is common in a range of immune-mediated inflammatory diseases, is seen in multiple vascular beds, and is reversible following the induction of disease remission. The mechanisms that drive such systemic vascular endothelial dysfunction are unclear but factors such as TNF-alpha and CRP may play a role. Persistence of such widespread endothelial dysfunction in systemic vasculitis appears to have long-term consequences, leading to the acceleration of atherosclerosis and premature ischaemic heart disease. It may also underlie the accelerated atherosclerosis seen in other immune-mediated rheumatic diseases, such as rheumatoid arthritis.     

Comparative evaluation of FGF-2-, VEGF-A-, and VEGF-C-induced angiogenesis, lymphangiogenesis, vascular fenestrations, and permeability

Several endothelial growth factors induce both blood and lymphatic angiogenesis. However, a systematic comparative study of the impact of these factors on vascular morphology and function has been lacking. In this study, we report a quantitative analysis of the structure and macromolecular permeability of FGF-2-, VEGF-A-, and VEGF-C-induced blood and lymphatic vessels. Our results show that VEGF-A stimulated formation of disorganized, nascent vasculatures as a result of fusion of blood capillaries into premature plexuses with only a few lymphatic vessels. Ultrastructural analysis revealed that VEGF-A-induced blood vessels contained high numbers of endothelial fenestrations that mediated high permeability to ferritin, whereas the FGF-2-induced blood vessels lacked vascular fenestrations and showed only little leakage of ferritin. VEGF-C induced approximately equal amounts of blood and lymphatic capillaries with endothelial fenestrations present only on blood capillaries, mediating a medium level of ferritin leakage into the perivascular space. No endothelial fenestrations were found in FGF-2-, VEGF-A-, or VEGF-C-induced lymphatic vessels. These findings highlight the structural and functional differences between blood and lymphatic vessels induced by FGF-2, VEGF-A, and VEGF-C. Such information is important to consider in development of novel therapeutic strategies using these angiogenic factors.     

Acetoacetate and beta-hydroxybutyrate differentially regulate endothelin-1 and vascular endothelial growth factor in mouse brain microvascular endothelial cells.

Insulin-dependent diabetes mellitus (IDDM), is characterized by a lack of insulin production from beta cells in the pancreas. One of the metabolic consequences of this insulin deficit is an increased hepatic synthesis of ketone bodies, resulting in a serious medical complication, diabetic ketoacidosis (DKA). DKA, in turn, has been associated with the development of cerebral edema. The severity of this complication ranges from death to a subclinical presentation, but seems to be invariably present to some degree. The etiology of the cerebral edema is unknown, but changes in osmolality, pH, and insulin effects on the blood-brain barrier have all been suggested as possible culprits. Blood-brain barrier impermeability is maintained by the endothelial cells (EC) lining the blood vessels. Thus, it would seem likely that alterations in EC function would be necessary for the development of cerebral edema. However, no studies have examined the effects of ketone bodies on brain endothelial cells. The two major ketone bodies in DKA are acetoacetate (AcAc) and beta-hydroxybutyrate (BOHB). In the present study we examined the effect of these ketone bodies on a major intracellular signalling pathway. The changes in intracellular calcium concentration, and the production of two vasoactive peptides, endothelin-1 (ET-1) and vascular permeability factor (VPF/VEGF) in mouse brain microvascular endothelial cells (MBMEC). The present studies demonstrate the BOHB can increase vascular permeability factor. In contrast, AcAc increases the production of the potent vasoconstrictor, endothelin-1. This data would suggest that brain ECs are potential targets of the metabolic alterations in DKA.     

机械门控阳离子通道Piezo1与动脉粥样硬化研究进展

Piezo1蛋白是一种非选择性机械门控阳离子通道,在机械刺激作用下,可以引起钙、钠、钾等阳离子内流,进而将机械信号转化为生物电信号,并将信号整合至细胞内,参与多种生理和病理过程。Piezo1蛋白广泛存在于心血管系统中,在血流剪切应力和血管张力传感、血管发育和新生、血管重塑等许多心血管活动中发挥重要作用。Piezo1可感受血流剪切应力和血管张力的变化,其表达也受到二者的影响,进而影响血管内皮细胞的形态、排列、合成、分泌、炎症和黏附等功能。Piezo1也可调控巨噬细胞的迁移、炎症反应和脂质吞噬等,参与调控动脉粥样硬化的发生发展。血管平滑肌细胞增殖同样受到Piezo1的调控,进而影响血管壁的重构。本文主要综述Piezo1通道的发现、结构和功能,以及在动脉粥样硬化方面的研究进展,以期为动脉粥样硬化的防治提供新的思路。