血管外膜原位干/祖细胞研究现状及进展

传统的观点认为血管外膜作为疏松结缔组织,包含了成纤维细胞、炎症细胞,滋养血管、神经末梢等,仅主要起到支撑、营养血管的作用.然而,近年越来越多的证据表明血管外膜中存在原位干/祖细胞.在病理情况下,这些血管壁原位干/祖细胞分化为内皮细胞或平滑肌细胞,从而参与动脉粥样硬化的进展、血管损伤后的修复与重构等.本文将对血管外膜原位干/祖细胞的研究现状及进展作一综述.     

血管外膜在调节血管张力中的作用

动脉壁有三层结构：内膜、中膜、外膜,每一层均具有独特的组织学、生物学及功能特征,并且每层以独特的方式来维持血管稳定及调节血管对各种刺激及损伤的反应。近20年,有关血管内膜对血管功能的影响得到深入广泛的研究,血管内膜在调节血管平滑肌功能中的作用已得到普遍的认同。血管外膜是非常复杂的一层,由较厚的致密结构组成,含有大量的胶原纤维和弹性纤维,细胞成分主要是成纤维细胞及少量平滑肌细胞。支配血管舒缩的交感及副交感神经纤维从外膜进入血管;滋养血管也从外膜进入,     

外膜滋养血管新生的病理机制

<正>外膜是集成血管壁功能的主要监管机构,可以充当生物"中央处理器",外膜分布有多种细胞能够发挥强效免疫调节作用,包括成纤维细胞、巨噬细胞、树突状细胞、祖细胞、滋养血管以及肾上腺素能神经。成纤维细胞的激活能够促进巨噬细胞、树突状细胞、祖细胞作用的发挥,创建一个持久的炎症反应的微环境,引起滋养血管的新生〔1〕。由于研究血管滋养管的适合方法有限,观察动脉壁上微血管新生的病理生理环境也知之甚少。本文就今年来关于外膜滋养血管(VV)新生的生理、病理     

内皮素转换酶、内皮素与糖尿病血管病变

内皮素是目前所知的最强的长效缩血管活性多肽 ,主要由血管内皮细胞合成。其通过自分泌、旁分泌或内分泌等作用 ,在正常生理活动及某些疾病 ,尤其是与血管病变有关的疾病的发生、发展中起重要作用。内皮素转换酶是内皮素生物合成的关键酶 ,在体内内皮素生物活性调节上起着极为重要的作用。糖尿病并发症繁多 ,血管并发症是其主要并发症及致死、致残的主要原因。因此 ,进行内皮素转换酶、内皮素与糖尿病血管病变的研究 ,探求内皮素转换酶、内皮素在其中的可能机制尤为必要。一、内皮素、内皮素转换酶的来源、结构内皮素 (endothelin,ET)于 19…     

血管外膜成纤维细胞与血管再狭窄

血管外膜成纤维细胞的迁移、增殖、胶原合成与分泌及其细胞表型转化是血管增殖性疾病中血管重构的重要病理学基础。血管再狭窄是目前心血管分子生物学研究领域的热点。对血管外膜成纤维细胞的研究可为血管再狭窄的治疗提供新的思路。     

血管旁脂肪组织与糖尿病大血管病变

糖尿病大血管病变是糖尿病患者致死、致残的首要原因,其主要的病理基础为动脉粥样硬化,但其机制尚未完全阐明.血管旁脂肪组织可分泌众多脂肪细胞因子,研究发现它们不仅参与肥胖、胰岛素抵抗的病理生理过程,还可通过旁分泌和滋养血管分泌“由外至内”作用于血管壁,调节血管张力并参与动脉粥样硬化的发生、发展过程.对血管旁脂肪组织的深入研...     

血管活性肽与阻塞性睡眠呼吸暂停综合征

血管活性肽是构成循环系统自稳态调节的物质基础,能够调节血管平滑肌细胞舒缩功能、维持血管张力,多数以自分泌、旁分泌方式发挥作用,并按其血管效应的不同分为缩血管肽和舒血管肽.生理条件下,血管舒-缩活性肽之间存在着复杂的正反馈或负反馈调节,由此构成一个精细、严密的血管张力调控网络.其平衡失调会导致冠状动脉粥样硬化性心脏病、高...     

单核/巨噬细胞在血管重塑中的作用

单核/巨噬细胞是血管重塑的重要参与者.在血管损伤时,激活的血管细胞产生炎症免疫反应招募炎症细胞,特别是单核/巨噬细胞到损伤部位进一步加速炎症的进程,这一过程在血管重塑中发挥至关重要的调控作用.血管损伤部位中的单核/巨噬细胞系主要来自于骨髓中的造血干细胞,血管外膜炎症反应为血管损伤过程的始发因素.     

血管外膜与动脉粥样硬化

动脉粥样硬化(AS)是一种由脂质沉积引起的血管系统多病灶慢性免疫炎性疾病,主要累及大、中动脉,其发病机制十分复杂.长期以来,对AS机制的研究主要集中在内膜和中膜.最近越来越多的研究表明,血管外膜与动脉硬化形成密切相关.现就血管外膜及其相关血管活性肽在AS发生中所起的作用作一综述.     

成纤维细胞活化在低氧性肺血管重构中的作用

以往在低氧性肺血管重构机制的研究中,外膜的作用往往被忽略。新近的研究表明,血管外膜特别是其中的成纤维细胞在调节血管功能中发挥着重要的作用。外膜中的成纤维细胞是低氧刺激的首要“损伤感受细胞”,低氧可以激活血管外膜成纤维细胞,活化的成纤维细胞既可以合成分泌细胞生长因子、炎症因子,进而促进中膜血管平滑肌细胞增殖,又可以转分化为平滑肌样细胞（肌纤维母细胞）、分泌胶原蛋白,导致血管重构。因此,低氧导致的成纤维细胞活化及表型转换在肺血管重构中起重要作用,贯穿着低氧性肺血管重构的整个病理过程。     

Adventitial fibroblast reactive oxygen species as autacrine and paracrine mediators of remodeling: bellwether for vascular disease?

The importance of the vascular adventitia is increasingly being recognized not only in vascular disease but also in normal maintenance and homeostasis of vessels. Activation of the adventitia and its resident fibrocytic cells in response to injury, stretch, cytokines, and hormones has been shown to stimulate differentiation, collagen deposition, migration, and proliferation. Importantly, the effects of adventitial fibroblasts are increasingly being ascribed to reactive oxygen species (ROS) produced by adventitial fibroblast NAD(P)H oxidases. Much historical and recent evidence suggests that fibroblast NAD(P)H oxidase) is a harbinger and initiator of vascular disease and remodeling. Data from our laboratory indicate that adventitial fibroblast NAD(P)H oxidase plays a direct and/or paracrine role in neointimal hyperplasia as well as a paracrine role in medial smooth muscle hypertrophy in vivo. We propose that adventitial NAD(P)H oxidase-derived cell-permeant hydrogen peroxide or a byproduct of its oxidation of lipids activates signaling mechanisms in medial smooth muscle leading to the growth response. This review will address the potential role of this adventitial ROS in vascular inflammation and cytokine release to potentiate smooth muscle hypertrophy. We will also survey other signaling pathways involving adventitial NAD(P)H oxidase ultimately leading to changes in vascular phenotype.     

交感神经系统在血管性疾病发生发展中的研究进展

交感神经系统通过释放各种交感神经递质直接参与血管正常生理功能的调节,对维持血管稳态具有重要作用.然而病理条件下交感神经系统的改变会影响血管张力以及血管的反应性等,从而导致高血压、动脉粥样硬化和肺动脉高压等血管性疾病.本文主要综述交感神经系统在相关血管性疾病的发生发展中的作用.     

Cell biology of vascular hypertrophy in systemic hypertension

Recent data demonstrate that in addition to its conduit function, the blood vessel is an active synthetic and secretory organ containing several autocrine and paracrine systems that are involved with the local regulation of its own function (i.e., structure and growth). The endothelium secretes vasorelaxant and vasoconstrictive substances, growth factors and inflammatory mediators that exert paracrine influences on vascular myocyte function. The vascular myocyte also expresses autocrine substances that influence its own function. The autocrine systems include angiotensin, prostaglandins, platelet-derived growth factor, insulin-like growth factor and heparin. These local factors exert modulatory influences on myocyte contractility and growth. These autocrine and paracrine systems serve as an adaptive mechanism by which the vasculature autoregulates its structural and functional state. We speculate that an alteration in this delicate balance of these local factors, due to genetic or acquired abnormalities, can result in increased vascular tone and vessel hypertrophy and thereby contribute to the pathogenesis of hypertension.     

The reactive adventitia: fibroblast oxidase in vascular function

The vascular adventitia is activated in a variety of cardiovascular disease states and has recently been shown to be a barrier to nitric oxide bioactivity. Vascular fibroblasts produce substantial amounts of NAD(P)H oxidase-derived reactive oxygen species (ROS) that appear to be involved in fibroblast proliferation, connective tissue deposition, and perhaps vascular tone. However, the physiological and pathophysiological roles of the adventitia have not been extensively studied, possibly because of its location in large blood vessels remote from the vascular endothelium. In recent years, substantial information has been gathered on pathways leading to oxidase activation in smooth muscle cells and fibroblasts and the downstream signaling pathways leading to hypertrophy and proliferation. A clearer understanding of the molecular mechanisms involved will likely lead to therapeutic strategies aimed at preventing vascular dysfunction in diseases such as atherosclerosis, in which these pathways are activated.     

Vascular endothelial growth factor and vascular homeostasis

Vascular endothelial growth factor (VEGF) is the angiogenic factor promoting and orchestrating most, if not all, processes of neovascularization taking place in the embryo and the adult. VEGF is also required to sustain newly formed vessels and plays additional multiple roles in the maintenance and function of certain mature vascular beds. Correspondingly, perturbations in VEGF signaling may impact organ homeostasis in multiple ways. Here we briefly review potential consequences of VEGF loss of function in adult organs. Different vascular beds display highly variable dependencies on VEGF for survival, and its loss of function may trigger the regression of many VEGF-dependent vasculatures. Normal turnover of blood vessels, in conjunction with the fact that VEGF is indispensable for compensatory angiogenesis to restore adequate perfusion, accounts for progressive vascular rarefaction under conditions of chronic VEGF inhibition of even vasculatures that are not intrinsically dependent on VEGF. Because blood vessels may have paracrine functions other than their traditional role in tissue perfusion, vascular regression resulting from VEGF withdrawal may cause substantial collateral tissue damage. VEGF may also impact tissue homeostasis via acting directly on nonvascular cells expressing cognate receptors. In the particular case of the lung, constitutive abundant expression of VEGF together with the fact that its receptors are distributed on both endothelial and epithelial cells is compatible with multiple homeostatic VEGF functions in the adult lung. Indeed, experimental inhibition of VEGF in the mature lung produces lesions resembling common lung pathologies, including emphysema and respiratory distress syndrome.     

Molecular and cellular basis of pulmonary vascular remodeling in pulmonary hypertension

Clinical pulmonary hypertension is characterized by a sustained elevation in pulmonary arterial pressure. Pulmonary vascular remodeling involves structural changes in the normal architecture of the walls of pulmonary arteries. The process of vascular remodeling can occur as a primary response to injury, or stimulus such as hypoxia, within the resistance vessels of the lung. Alternatively, the changes seen in more proximal vessels may arise secondary to a sustained increase in intravascular pressure. To withstand the chronic increase in intraluminal pressure, the vessel wall becomes thickened and stronger. This "armouring" of the vessel wall with extra-smooth muscle and extracellular matrix leads to a decrease in lumen diameter and reduced capacity for vasodilatation. This maladaptive response results in increased pulmonary vascular resistance and consequently, sustained pulmonary hypertension. The process of pulmonary vascular remodeling involves all layers of the vessel wall and is complicated by the finding that cellular heterogeneity exists within the traditional compartments of the vascular wall: intima, media, and adventitia. In addition, the developmental stage of the organism greatly modifies the response of the pulmonary circulation to injury. This review focuses on the latest advances in our knowledge of these processes as they relate to specific forms of pulmonary hypertension and particularly in the light of recent genetic studies that have identified specific pathways involved in the pathogenesis of severe pulmonary hypertension.     

Targeting the vascular endothelial growth factor in hematologic malignancies

There exists increasing evidence that apart from solid tumors, angiogenic growth factors also play important roles in the development and/or maintenance of hematolymphoid malignancies. Thus, in these cancers, angiogenesis and bone marrow microvessel density often correlate with prognosis and disease burden. Several reports speculated on the role of angiogenesis and the resulting possible therapeutic options in hematologic malignancies. The most prominent angiogenic factor, vascular endothelial growth factor (VEGF), is expressed in a number of established leukemic cell lines as well as in freshly isolated human leukemias and lymphomas, and several human leukemias express VEGF receptor 1 and/or VEGF receptor 2. VEGF/VEGF‐receptor interactions are also involved in proliferation, migration, and survival of leukemic cells by autocrine and paracrine mechanisms. As a consequence, a possible drugable effect by inhibiting VEGF signaling in different hematologic malignancies has been discussed. This review focuses on angiogenesis‐independent effects of VEGF on survival and proliferation of leukemic or lymphoma cells and on possible therapeutic approaches using anti‐VEGF/VEGF‐receptor therapies to inhibit proliferation or induce apoptosis of malignant cells in hematologic diseases.     

Autocrine-paracrine mechanisms of vascular myocytes in systemic hypertension

Recent data demonstrate that in addition to its conduit function, the blood vessel is an active synthetic and secretory organ containing several autocrine and paracrine systems that are involved with the local regulation of its own function. The endothelium plays a pivotal role in modulating the balance between thrombogenesis and thrombolysis. In addition, it secretes vasorelaxant and vasoconstrictive substances, growth factors and inflammatory mediators that exert paracrine influences on vascular myocyte function. The vascular myocyte also expresses autocrine substances which influence its own function. The autocrine systems include angiotensin, prostaglandins, platelet-derived growth factor, insulin-like growth factor and heparin. These local factors exert modulatory influences on myocyte contractility and growth. It is conceivable that genetic or acquired abnormalities of one or several of these check and balance systems can result in increased vascular tone, generalized vascular hypertrophy or hyperplasia, or a combination, and contribute to the pathogenesis of hypertension. These autocrine-paracrine systems may be important targets for antihypertensive drug development.     

Autocrine/paracrine involvement of parathyroid hormone-related peptide in vascular leiomyoma

Vascular leiomyomas are believed to arise from the smooth muscle of blood vessels and are characterized by the proliferation of vascular smooth muscle cells (VSMC) and numerous slit-like vascular lumens. Parathyroid hormone (PTH)-related peptide (PTHrP) plays an important role in local autocrine and/or paracrine regulation of cellular growth and function in VSMC. To investigate the interaction between VSMC and endothelial cells, we evaluated the distribution of PTHrP and PTH/PTHrP-receptor in 10 vascular leiomyomas of the skin by immunohistochemistry and in situ hybridization (ISH) of paraffin-embedded specimens. Both immunohistochemistry and ISH revealed that PTH/PTHrP-receptors are expressed in endothelial cells lining areas with slit-like vascular lumens and very weakly expressed in proliferating VSMC in all vascular leiomyomas. On the other hand, PTHrP itself was localized mainly in proliferating VSMC. These results support the hypothesis that PTHrP acts through the PTH/PTHrP-receptor via an autocrine and/or paracrine mechanism from VSMC to endothelial cells in the formation of characteristic microenvironments of vascular leiomyoma cell composition.     

Adrenomedullin in vascular diseases

A novel vasodilator, adrenomedullin (AM), which acts as an autocrine/paracrine factor in cardiovascular system, has antiproliferative and antimigrative effects. AM gene transfer prevents the development of cuff-induced vascular injury. Moreover, AM knockout mice exhibited an increase in angiotensin (Ang) II/salt loading-induced coronary arterial lesion, hypoxia-induced pulmonary vascular damage, and cuff-induced vascular injury associated with enhancement in reactive oxygen species (ROS) generation. In addition, AM expression was stimulated by ROS, and AM directly inhibits oxidative stress so that AM might be a negative feedback substance against ROS-induced organ damages. In addition, AM increases nitric oxide and ameliorates insulin resistance, leading to oxidative stress. Consequently, endogenous AM might compensatively inhibit the development of vascular diseases at least partly through an antioxidative effect.