64排CT血管造影在脑动静脉畸形诊断中的价值

目的：探讨64排CT血管造影（computedtomography angiographycTA）对脑动静脉畸形（cerebral arefiovenousmalformation,AVM）的诊断价值。方法：16例AVM患者,均行64排螺旋CT血管造影检查,使用多种重建方法,由两名有经验的医生对畸形血管团进行分析。结果：16例均为单发瘤巢,16例AVM均显示了大小不等的畸形血管团及供血动脉和引流静脉,其中,2例同时伴脑出血（12．5％）,3例有出血后软化灶形成（18．75％）,16例发现有供血动脉31支,16例发现有明确的引流静脉21支。结论：64排CTA安全．快速．结合多种重建方法．可以清晰显示AVM的供血动脉、瘤巢．引流静脉．为临床治疗提供了可靠的信息．     

Interaction between alk1 and blood flow in the development of arteriovenous malformations

Arteriovenous malformations (AVMs) are fragile direct connections between arteries and veins that arise during times of active angiogenesis. To understand the etiology of AVMs and the role of blood flow in their development, we analyzed AVM development in zebrafish embryos harboring a mutation in activin receptor-like kinase I (alk1), which encodes a TGFβ family type I receptor implicated in the human vascular disorder hereditary hemorrhagic telangiectasia type 2 (HHT2). Our analyses demonstrate that increases in arterial caliber, which stem in part from increased cell number and in part from decreased cell density, precede AVM development, and that AVMs represent enlargement and stabilization of normally transient arteriovenous connections. Whereas initial increases in endothelial cell number are independent of blood flow, later increases, as well as AVMs, are dependent on flow. Furthermore, we demonstrate that alk1 expression requires blood flow, and despite normal levels of shear stress, some flow-responsive genes are dysregulated in alk1 mutant arterial endothelial cells. Taken together, our results suggest that Alk1 plays a role in transducing hemodynamic forces into a biochemical signal required to limit nascent vessel caliber, and support a novel two-step model for HHT-associated AVM development in which pathological arterial enlargement and consequent altered blood flow precipitate a flow-dependent adaptive response involving retention of normally transient arteriovenous connections, thereby generating AVMs.     

VEGF-A, cytoskeletal dynamics, and the pathological vascular phenotype

Normal angiogenesis is a complex process involving the organization of proliferating and migrating endothelial cells (ECs) into a well-ordered and highly functional vascular network. In contrast, pathological angiogenesis, which is a conspicuous feature of tumor growth, ischemic diseases, and chronic inflammation, is characterized by vessels with aberrant angioarchitecture and compromised barrier function. Herein we review the subject of pathological angiogenesis, particularly that driven by vascular endothelial growth factor (VEGF-A), from a new perspective. We propose that the serious structural and functional anomalies associated with VEGF-A-elicited neovessels, reflect, at least in part, imbalances in the internal molecular cues that govern the ordered assembly of ECs into three dimensional vascular networks and preserve vessel barrier function. Adopting such a viewpoint widens the focus from solely on specific pro-angiogenic stimuli such as VEGF-A to include a key set of cytoskeletal regulatory molecules, the Rho GTPases, which are known to direct multiple aspects of vascular morphogenesis including EC motility, alignment, multi-cellular organization, as well as intercellular junction integrity. We offer this perspective to draw attention to the importance of endothelial cytoskeletal dynamics for proper neovascularization and to suggest new therapeutic strategies with the potential to improve the pathological vascular phenotype.     

儿童颈髓区巨大动静脉畸形1例(英文)

脑动静脉畸形(AVM)是复杂的血管病变,是由于没有毛细血管床的脑动脉和静脉之间的异常连接引起的病灶[1]。脑动静脉畸形的临床表现有大出血、癫痫、神经功能障碍或头痛,但大部分患者无特异性症状,因此容易漏诊、误诊。手术切除、血管内治疗和放射治疗是动静脉畸形的选择疗法。血管内治疗可以作为其他难以治愈的脑动静脉畸形,或者作为手术切除或放射治疗前的辅助治疗,以减少脑动静脉畸形的血供或促进其收缩,进而促进手术切除或消融[2]。该病引起的颈部疼痛在儿科未见报道。我们收治1例颈髓区巨大动静脉畸形患儿,表现为持续性颈部疼痛并出现癫痫和呕吐症状,经采取分段外科胶栓塞术(第一次部分栓塞术后观察1年再行第二次栓塞),达到动静脉畸形的治愈。     

Anti-HLA I antibodies induce VEGF production by endothelial cells,which increases proliferation and paracellular permeability

Anti-human leukocyte antigen class I (HLA I) antibodies were shown to activate several protein kinases in endothelial cells (ECs), which induces proliferation and cell survival. An important phenomenon in antibody-mediated rejection is the occurrence of interstitial edema. We investigated the effect of anti-HLA I antibodies on endothelial proliferation and permeability, as one possible underlying mechanism of edema formation. HLA I antibodies increased the permeability of cultured ECs isolated from umbilical veins. Anti-HLA I antibodies induced the production of vascular endothelial growth factor (VEGF) by ECs, which activated VEGF receptor 2 (VEGFR2) in an autocrine manner. Activated VEGFR2 led to a c-Src-dependent phosphorylation of vascular endothelial (VE)-cadherin and its degradation. Aberrant VE-cadherin expression resulted in impaired adherens junctions, which might lead to increased endothelial permeability. This effect was only observed after cross-linking of HLA I molecules by intact antibodies. Furthermore, our results suggest that increased endothelial proliferation following anti-HLA I treatment occurs via autocrine VEGFR2 activation. Our data indicate the ability of anti-HLA I to induce VEGF production in ECs. Transactivation of VEGFR2 leads to increased EC proliferation and paracellular permeability. The autocrine effect of VEGF on endothelial permeability might be an explanation for the formation of interstitial edema after transplantation.     

脑血管畸形破裂出血的影响因素及受试者工作特征曲线预测价值分析

目的:探讨脑血管畸形破裂出血的影响因素,并进行受试者工作特征(ROC)曲线分析。方法:回顾性分析我院2015年6月至2018年1月收治的138例脑血管畸形患者的临床资料,根据患者是否并发破裂出血,将其分为出血组(n=76)和未出血组(n=62)。采用单因素和多因素Logistic回归分析法对两组患者的临床资料进行研究,并采用ROC曲线评价各影响因素对脑血管畸形破裂出血的预测价值。结果:两组患者在与畸形血管团位置关系、是否合并硬脑膜动静脉瘘、合并动脉瘤数目、合并动脉瘤大小、合并瘤样变、供血动脉位置、引流静脉方向以及畸形血管团大小方面差异具有统计学意义(P0.05)。多因素Logistic回归分析结果显示,引流静脉方向、畸形血管团大小以及合并动脉瘤数目是脑血管畸形破裂出血的独立危险因素(P0.05)。引流静脉方向的ROC曲线下面积为0.921,特异度和灵敏度分别为0.832和0.801,是三种影响因素中预测价值最高的,其次是合并动脉瘤数目和畸形血管团大小。结论:合并动脉瘤、引流静脉方向以及畸形动脉血管团大小是脑血管畸形破裂出血的重要危险因素,且对脑血管畸形破裂出血具有一定的预测价值,可为脑血管畸形破裂出血的预防诊治提供参考。     

IL-10 Accelerates Re-Endothelialization and Inhibits Post-Injury Intimal Hyperplasia following Carotid Artery Denudation

The role of inflammation on atherosclerosis and restenosis is well established. Restenosis is thought to be a complex response to injury, which includes early thrombus formation, acute inflammation and neo-intimal growth. Inflammatory cells are likely contributors in the host response to vascular injury, via cytokines and chemokines secretion, including TNF-alpha (TNF). We have previously shown that IL-10 inhibits TNF and other inflammatory mediators produced in response to cardiovascular injuries. The specific effect of IL-10 on endothelial cell (ECs) biology is not well elucidated. Here we report that in a mouse model of carotid denudation, IL-10 knock-out mice (IL-10KO) displayed significantly delayed Re-endothelialization and enhanced neo-intimal growth compared to their WT counterparts. Exogenous recombinant IL-10 treatment dramatically blunted the neo-intimal thickening while significantly accelerating the recovery of the injured endothelium in WT mice. In vitro, IL-10 inhibited negative effects of TNF on ECs proliferation, ECs cell cycle, ECs-monocyte adhesion and ECs apoptosis. Furthermore, IL-10 treatment attenuated TNF-induced smooth muscle cells proliferation. Our data suggest that IL-10 differentially regulate endothelial and vascular smooth cells proliferation and function and thus inhibits neo-intimal hyperplasia. Thus, these results may provide insights necessary to develop new therapeutic strategies to limit vascular restenosis during percutaneous coronary intervention (PCI) in the clinics.     

Endothelial microvesicles in hypoxic hypoxia diseases

Hypoxic hypoxia, including abnormally low partial pressure of inhaled oxygen, external respiratory dysfunction‐induced respiratory hypoxia and venous blood flow into the arterial blood, is characterized by decreased arterial oxygen partial pressure, resulting in tissue oxygen deficiency. The specific characteristics include reduced arterial oxygen partial pressure and oxygen content. Hypoxic hypoxia diseases (HHDs) have attracted increased attention due to their high morbidity and mortality and mounting evidence showing that hypoxia‐induced oxidative stress, coagulation, inflammation and angiogenesis play extremely important roles in the physiological and pathological processes of HHDs‐related vascular endothelial injury. Interestingly, endothelial microvesicles (EMVs), which can be induced by hypoxia, hypoxia‐induced oxidative stress, coagulation and inflammation in HHDs, have emerged as key mediators of intercellular communication and cellular functions. EMVs shed from activated or apoptotic endothelial cells (ECs) reflect the degree of ECs damage, and elevated EMVs levels are present in several HHDs, including obstructive sleep apnoea syndrome and chronic obstructive pulmonary disease. Furthermore, EMVs have procoagulant, proinflammatory and angiogenic functions that affect the pathological processes of HHDs. This review summarizes the emerging roles of EMVs in the diagnosis, staging, treatment and clinical prognosis of HHDs.     

Statins attenuate high mobility group box-1 protein induced vascular endothelial activation : a key role for TLR4/NF-κB signaling pathway

High mobility group box-1 (HMGB1) has recently been implicated as a proinflammatory cytokine that plays critical roles in endothelial dysfunction and atherosclerosis. Atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, exerts anti-inflammatory effects in the cardiovascular system beyond its cholesterol-lowering property. The aim of our study was to investigate whether atorvastatin inhibits HMGB1-induced vascular endothelial activation, and elucidate the underlying molecular mechanism. In this study, we found that atorvastatin, at concentrations ranging from 0.1 to 10 μM, effectively and in a dose-dependent manner inhibited HMGB1-induced endothelial cells (ECs) activation. Incubation of ECs with 10 μM atorvastatin reduced adhesion molecules (ICAM-1 and E-selectin) expression concomitant with a significant inhibition in HMGB1-stimulated leukocyte-endothelial adhesion. Further experiments showed that atorvastatin markedly suppressed HMGB1-induced Toll like receptor 4 (TLR4) expression, Nuclear factor kappaB (NF-κB) nuclear translocation and DNA binding activity in ECs. Similar effects were also observed in ECs pretreated with the TLR4- specific inhibitor CLI-095, suggesting an important role of TLR4/NF-κB pathway. These findings indicate that atorvastatin attenuates HMGB1-induced vascular endothelial activation. The underlying mechanism involves, at least in part, inhibition of TLR4/NF-κB-dependent signaling pathway, which provied the new evidence for therapeutic application of statins to target inflammatory processes in cardiovascular disease.     

ACE inhibition and atherogenesis

Recent clinical studies such as HOPE, SECURE, and APRES show that angiotensin-converting enzyme (ACE) inhibitors like ramipril improve the prognosis of patients with a high risk of atherothrombotic cardiovascular events. Atherosclerosis, as a chronic inflammatory condition of the vascular system, can turn into an acute clinical event through the rupture of a vulnerable atherosclerotic plaque followed by thrombosis. ACE inhibition has a beneficial effect on the atherogenic setting and on fibrinolysis. Endothelial dysfunction is the end of a common process in which cardiovascular risk factors contribute to inflammation and atherogenesis. By inhibiting the formation of angiotensin II, ACE inhibitors prevent any damaging effects on endothelial function, vascular smooth muscle cells, and inflammatory vascular processes. An increase in the release of NO under ACE inhibition has a protective effect. Local renin-angiotensin systems in the tissue are involved in the inflammatory processes in the atherosclerotic plaque. Circulating ACE-containing monocytes, which adhere to endothelial cell lesions, differentiate within the vascular wall to ACE-containing macrophages or foam cells with increased local synthesis of ACE and angiotensin II. Within the vascular wall, angiotensin II decisively contributes to the instability of the plaque by stimulating growth factors, adhesion molecules, chemotactic proteins, cytokines, oxidized LDL, and matrix metalloproteinases. Suppression of the increased ACE activity within the plaque can lead to the stabilization and deactivation of the plaque by reducing inflammation in the vascular wall, thus lessening the risk of rupture and thrombosis and the resultant acute clinical cardiovascular events. The remarkable improvement in the long-term prognosis of atherosclerotic patients with increased cardiovascular risk might be the clinical result of the contribution made by ACE inhibition in the vascular wall.     

Endothelial microparticles act as novel diagnostic and therapeutic biomarkers of circulatory hypoxia‐related diseases: a literature review

Circulatory hypoxia‐related diseases (CHRDs), including acute coronary syndromes, stroke and organ transplantation, attract increased attention due to high morbidity and mortality. Mounting evidence shows that hypoxia‐induced oxidative stress, coagulation, inflammation and angiogenesis play extremely important roles in the physiological and pathological processes of CHRD‐related vascular endothelial injury. Interestingly, hypoxia, even hypoxia‐induced oxidative stress, coagulation and inflammation can all induce release of endothelial microparticles (EMPs). EMPs, shed from activated or apoptotic endothelial cells (ECs), reflect the degree of EC damage, and elevated EMP levels are found in several CHRDs. Furthermore, EMPs, which play an important role in cell‐to‐cell communication and function, have confirmed pro‐coagulant, proinflammatory, angiogenic and other functions, affecting pathological processes. These findings suggest that EMPs and CHRDs have a very close relationship, and EMPs may help to identify CHRD phenotypes and stratify the severity of disease, to improve risk stratification for developing CHRDs, to better define prophylactic strategies and to ameliorate prognostic characterization of patients with CHRDs. This review summarizes the known and potential roles of EMPs in the diagnosis, staging, treatment and clinical prognosis of CHRDs.     

内皮祖细胞在炎症损伤修复中的作用和机制

内皮祖细胞（endothelial progenitor cells,EPCs）是出生后,可以在机体内分化为成熟内皮细胞的一种前体细胞,主要来源于骨髓。多种伴有血管内皮细胞损伤的疾病都可引起外周血EPCs数量变化。有研究显示EPCs参与炎性损伤修复,并且外周血EPCs数量与血管内皮损伤程度和疾病预后存在一定的相关关系。EPCs。通过动员、迁移、归巢和分化等步骤修复内皮。炎症反应中受损组织释放的基质细胞衍生因子、血管内皮生长因子可与EPCs相应的受体结合,通过内皮型一氧化氮合酶、基质金属蛋白酶9等途径调节内皮修复过程,这是EPCs分化为内皮细胞过程的主要调控机制。此外,EPCs还可通过旁分泌机制促进相邻的内皮细胞增殖分化。目前,EPCs在炎症领域仅用于内皮炎性损伤和疾病预后评估,但是EPCs在心血管疾病和组织工程领域应用研究的成功,为EPCs在炎症反应的诊断和治疗提供了新的思路。     

Interleukin-35 Inhibits Endothelial Cell Activation by Suppressing MAPK-AP-1 Pathway

Vascular response is an essential pathological mechanism underlying various inflammatory diseases. This study determines whether IL-35, a novel responsive anti-inflammatory cytokine, inhibits vascular response in acute inflammation. Using a mouse model of LPS-induced acute inflammation and plasma samples from sepsis patients, we found that IL-35 was induced in the plasma of mice after LPS injection as well as in the plasma of sepsis patients. In addition, IL-35 decreased LPS-induced proinflammatory cytokines and chemokines in the plasma of mice. Furthermore, IL-35 inhibited leukocyte adhesion to the endothelium in the vessels of lung and cremaster muscle and decreased the numbers of inflammatory cells in bronchoalveolar lavage fluid. Mechanistically, IL-35 inhibited the LPS-induced up-regulation of endothelial cell (EC) adhesion molecule VCAM-1 through IL-35 receptors gp130 and IL-12Rβ2 via inhibition of the MAPK-activator protein-1 (AP-1) signaling pathway. We also found that IL-27, which shares the EBI3 subunit with IL-35, promoted LPS-induced VCAM-1 in human aortic ECs and that EBI3-deficient mice had similar vascular response to LPS when compared with that of WT mice. These results demonstrated for the first time that inflammation-induced IL-35 inhibits LPS-induced EC activation by suppressing MAPK-AP1-mediated VCAM-1 expression and attenuates LPS-induced secretion of proinflammatory cytokines/chemokines. Our results provide insight into the control of vascular inflammation by IL-35 and suggest that IL-35 is an attractive novel therapeutic reagent for sepsis and cardiovascular diseases.     

Crimean-Congo hemorrhagic fever virus activates endothelial cells

Crimean-Congo hemorrhagic fever virus (CCHFV) causes viral hemorrhagic fever with high case-fatality rates and is geographically widely distributed. Due to the requirement for a biosafety level 4 (BSL-4) laboratory and the lack of an animal model, knowledge of the viral pathogenesis is limited. Crimean-Congo hemorrhagic fever (CCHF) is characterized by hemorrhage and vascular permeability, indicating the involvement of endothelial cells (ECs). The interplay between ECs and CCHFV is therefore important for understanding the pathogenesis of CCHF. In a previous study, we found that CCHFV-infected monocyte-derived dendritic cells (moDCs) activated ECs; however, the direct effect of CCHFV on ECs was not investigated. Here, we report that ECs are activated upon infection, as demonstrated by upregulation of mRNA levels for E-selectin, vascular cell adhesion molecule 1 (VCAM1), and intercellular adhesion molecule 1 (ICAM1). Protein levels and cell surface expression of ICAM1 responded in a dose-dependent manner to increasing CCHFV titers with concomitant increase in leukocyte adhesion. Furthermore, we examined vascular endothelial (VE) cadherin in CCHFV-infected ECs by different approaches. Infected ECs released higher levels of interleukin 6 (IL-6) and IL-8; however, stimulation of resting ECs with supernatants derived from infected ECs did not result in increased ICAM1 expression. Interestingly, the moDC-mediated activation of ECs was abrogated by addition of neutralizing tumor necrosis factor alpha (TNF-α) antibody to moDC supernatants, thereby identifying this soluble mediator as the key cytokine causing EC activation. We conclude that CCHFV can exert both direct and indirect effects on ECs.     

Topological Localization of Monomeric C-reactive Protein Determines Proinflammatory Endothelial Cell Responses

The activation of endothelial cells (ECs) by monomeric C-reactive protein (mCRP) has been implicated in contributing to atherogenesis. However, the potent proinflammatory actions of mCRP on ECs in vitro appear to be incompatible with the atheroprotective effects of mCRP in a mouse model. Because mCRP is primarily generated within inflamed tissues and is rapidly cleared from the circulation, we tested whether these discrepancies can be explained by topological differences in response to mCRP within blood vessels. In a Transwell culture model, the addition of mCRP to apical (luminal), but not basolateral (abluminal), surfaces of intact human coronary artery EC monolayers evoked a significant up-regulation of MCP-1, IL-8, and IL-6. Such polarized stimulation of mCRP was observed consistently regardless of EC type or experimental conditions (e.g. culture of ECs on filters or extracellular matrix-coated surfaces). Accordingly, we detected enriched lipid raft microdomains, the major surface sensors for mCRP on ECs, in apical membranes, leading to the preferential apical binding of mCRP and activation of ECs through the polarized induction of the phospholipase C, p38 MAPK, and NF-κB signaling pathways. Furthermore, LPS and IL-1β induction of EC activation also exhibited topological dependence, whereas TNF-α did not. Together, these results indicate that tissue-associated mCRP likely contributes little to EC activation. Hence, topological localization is an important, but often overlooked, factor that determines the contribution of mCRP and other proinflammatory mediators to chronic vascular inflammation.     

Retinal pigment epithelium-derived transforming growth factor-β2 inhibits the angiogenic response of endothelial cells by decreasing vascular endothelial growth factor receptor-2 expression

Transforming growth factor-β (TGF-β) is a multifunctional cytokine that is known to modulate various aspects of endothelial cell (EC) biology. Retinal pigment epithelium (RPE) is important for regulating angiogenesis of choriocapillaris and one of the main cell sources of TGF-β secretion, particularly TGF-β2. However, it is largely unclear whether and how TGF-β2 affects angiogenic responses of ECs. In the current study, we demonstrated that TGF-β2 reduces vascular endothelial growth factor receptor-2 (VEGFR-2) expression in ECs and thereby inhibits vascular endothelial growth factor (VEGF) signaling and VEGF-induced angiogenic responses such as EC migration and tube formation. We also demonstrated that the reduction of VEGFR-2 expression by TGF-β2 is due to the suppression of JNK signaling. In coculture of RPE cells and ECs, RPE cells decreased VEGFR-2 levels in ECs and EC migration. In addition, we showed that TGF-β2 derived from RPE cells is involved in the reduction of VEGFR-2 expression and inhibition of EC migration. These results suggest that TGF-β2 plays an important role in inhibiting the angiogenic responses of ECs during the interaction between RPE cells and ECs and that angiogenic responses of ECs may be amplified by a decrease in TGF-β2 expression in RPE cells under pathologic conditions.