Notch1信号通路与血管钙化

Notch1信号通路是一个高度保守的信号转导通路,参与胚胎期血管的形成及发育以及出生后对损伤血管的修复等。血管钙化是羟基磷灰石在血管壁细胞的沉积,受多种调节因子、信号通路影响,是一个可主动调节、类似于骨形成的生物学过程。近年来研究表明Notch1信号通路与血管钙化存在密切关系。本文就Notch1信号通路的组成、效应传递及生理功能,血管钙化的发生机制及调节,以及Notch1信号通路与血管钙化的关系作一综述。     

血管平滑肌细胞增殖、迁移的相关信号转导机制

血管平滑肌细胞(VSMC)向内膜增殖和迁移是动脉粥样硬化斑快形成、高血压、血管再狭窄等疾病的共同发病基础之一,多种信号转导通路参与了VSMC增殖、迁移,因此研究相关信号转导机制对上述疾病的防治有重要意义.     

血管平滑肌细胞增殖、迁移的相关信号转导机制

血管平滑肌细胞(VSMC)向内膜增殖和迁移是动脉粥样硬化斑快形成、高血压、血管再狭窄等疾病的共同发病基础之一,多种信号转导通路参与了VSMC增殖、迁移,因此研究相关信号转导机制对上述疾病的防治有重要意义。     

Notch通路与支气管哮喘相关的研究进展

近年来大量研究表明Notch通路在支气管哮喘(哮喘)的发生、发展中有十分重要的作用。Notch通路调控肺组织的发生发育,可以决定细胞的分化方向、调控肺泡和肺血管的发育;Notch通路参与T细胞调节,通过改变Th1/Th2平衡,影响Th17、Treg、树突状细胞表达等途径,导致哮喘的发生、发展;Notch通路也通过改变各...     

肺动脉平滑肌细胞与低氧性肺血管重塑形成机制

低氧条件下肺血管收缩、重塑,继而导致肺血管的持续对抗,其中以中膜增厚为主的肺血管重塑是导致低氧性肺动脉高压持续不可逆性病理改变的重要因素.肺动脉平滑肌细胞是肺动脉中膜的主要构成部分,慢性缺氧条件下由于各种活性介质及细胞生长因子稳态的失衡,肺动脉平滑肌细胞聚集、增殖、肥大及分泌胞外基质;另外,肺动脉平滑肌细胞通过各种信号通路与内膜的内皮细胞及外膜的成纤维细胞相互作用,在低氧性肺血管重塑过程中起着至关重要的作用,本文将对肺动脉平滑肌细胞与低氧性肺血管重塑形成机制的最新研究概况作一综述.     

Notch信号通路与血管生成

Notch通路为细胞发育的重要信号传导通路。研究显示在血管内皮、平滑肌细胞均存在不同程度的Notch家族基因表达，其成员相互作用，在细胞增殖、分化等诸多方面起重要调控作用。本文对Notch信号通路的组成及其与血管生成的关系作一综述，以进一步了解血管生成的机制。     

Notch信号通路及其在支气管哮喘中的作用

Notch信号通路参与多种组织细胞的分化成熟过程,尤其在外周T细胞的分化过程中起了决定性的作用,参与多种过敏性疾病(如支气管哮喘)的发生发展.近来研究表明Notch信号通路还参与诱发支气管哮喘的气道高反应性和促进气道黏液细胞增生.本文就Notch信号转导通路与支气管哮喘的关系作一综述.     

Notch信号通路及其在支气管哮喘中的作用

Notch信号通路参与多种组织细胞的分化成熟过程,尤其在外周T细胞的分化过程中起了决定性的作用,参与多种过敏性疾病(如支气管哮喘)的发生发展.近来研究表明Notch信号通路还参与诱发支气管哮喘的气道高反应性和促进气道黏液细胞增生.本文就Notch信号转导通路与支气管哮喘的关系作一综述.     

血小板源性生长因子及其受体在心血管疾病中的作用

血小板源性生成因子（PDGFs）及其受体（PDGFRs）在心血管疾病中发挥着重要作用,二者不仅参与了动脉粥样硬化（AS）的形成,而且在血管生成、心肌纤维化过程中也扮演了重要角色。PDGFRs被其配体PDGFs激活后,在血管平滑肌细胞、纤维母细胞、内皮细胞等中的表达上调,通过细胞内信号转导通路,促使该类靶细胞增殖分化,从而参与AS、血管生成和心肌纤维化的发生。本文就PDGFs/PDGFRs在心血管疾病中的研究进展做一综述。     

JAK/STAT信号通路调控血管平滑肌细胞病理生理功能的分子机制

转录信号传导子及激活子(STATs)信号转导途径是当前心血管分子生物学领域的研究热点.血管平滑肌细胞的增殖和迁移是血管增殖性疾病发病的核心环节,对其与STAT信号通路关系的研究,将为揭示血管新生内膜形成、血管重塑等病理机制提供新的研究方向,本文就以此信号通路为靶点,探讨其在血管平滑肌细胞的分子病理生理学作用特点.     

氧化应激和肺动脉高压血管重构

氧化应激可通过促进肺动脉血管平滑肌细胞增殖、加重血管内皮功能损伤和促进血管外基质增生等多条途径参与肺动脉血管重构,加速肺动脉高压的发生发展进程。近来研究发现,针对氧化应激进行的抗氧化治疗可有效地抑制肺动脉血管重构及肺动脉高压的发生,进一步证明了氧化应激在肺动脉血管重构乃至肺动脉高压中的重要作用。阐明病理条件下氧化还原信号途径,寻找抗氧化治疗的特异性药物,是肺动脉高压抗氧化治疗的基础和研究方向。     

内皮细胞凋亡与肺动脉高压

随着肺动脉高压研究的不断深入,肺血管内皮细胞凋亡在肺动脉高压形成过程中的重要作用被逐步认识。多种疾病和环境因素导致肺血管内皮损伤、内皮细胞凋亡增加、功能障碍,从而促进肺动脉平滑肌细胞和成纤维细胞增殖、肺动脉重构和血栓形成;肺血管内皮细胞凋亡还诱导产生凋亡抵抗表型的内皮细胞过度增殖,形成丛样病变和肺血管闭塞,最终导致严重肺动脉高压。因而在肺动脉高压发生发展的不同时期,调控肺血管内皮细胞凋亡可能是预防和治疗肺动脉高压的一种新策略。     

血管内皮生长因子在肺动脉平滑肌细胞重构中的作用

目的 :探讨血管内皮生长因子 （VEGF）在野百合碱 （MCT）性肺动脉高压 （PH）中的作用。方法 :用 MCT复制大鼠慢性 PH病理模型 ,用免疫组化法和图像分析技术测定肺组织中 VEGF的表达。结果 :发现 VEGF可在正常大鼠肺血管平滑肌、支气管平滑肌和软骨组织中表达 ,并且 MCT组 VEGF表达的相对含量在肺血管平滑肌 （177±7）和支气管平滑肌 （172± 6）均较正常组 （血管平滑肌 13 6± 8,支气管平滑肌 13 8± 12 ）呈显著增强 （P<0 .0 5）。结论 :MCT性 PH中 VEGF在肺血管平滑肌的过度表达参与 MCT性 PH的发病过程     

Key role of 15-lipoxygenase/15-hydroxyeicosatetraenoic acid in pulmonary vascular remodeling and vascular angiogenesis associated with hypoxic pulmonary hypertension

We have found that 15-hydroxyeicosatetraenoic acid (15-HETE) induced by hypoxia was an important mediator in the regulation of hypoxic pulmonary hypertension, including the pulmonary vasoconstriction and remodeling. However, the underlying mechanisms of the remodeling induced by 15-HETE are poorly understood. In this study, we performed immunohistochemistry, pulmonary artery endothelial cells migration and tube formation, pulmonary artery smooth muscle cells bromodeoxyuridine incorporation, and cell cycle analysis to determine the role of 15-HETE in hypoxia-induced pulmonary vascular remodeling. We found that hypoxia induced pulmonary vascular medial hypertrophy and intimal endothelial cells migration and angiogenesis, which were mediated by 15-HETE. Moreover, 15-HETE regulated the cell cycle progression and made more smooth muscle cells from the G(0)/G(1) phase to the G(2)/M+S phase and enhanced the microtubule formation in cell nucleus. In addition, we found that the Rho-kinase pathway was involved in 15-HETE-induced endothelial cells tube formation and migration and smooth muscle cell proliferation. Together, these results show that 15-HETE mediates hypoxia-induced pulmonary vascular remodeling and stimulates angiogenesis via the Rho-kinase pathway.     

Bone morphogenetic protein 4 promotes pulmonary vascular remodeling in hypoxic pulmonary hypertension

We show that 1 of the type II bone morphogenetic protein (BMP) receptor ligands, BMP4, is widely expressed in the adult mouse lung and is upregulated in hypoxia-induced pulmonary hypertension (PH). Furthermore, heterozygous null Bmp4(lacZ/+) mice are protected from the development of hypoxia-induced PH, vascular smooth muscle cell proliferation, and vascular remodeling. This is associated with a reduction in hypoxia-induced Smad1/5/8 phosphorylation and Id1 expression in the pulmonary vasculature. In addition, pulmonary microvascular endothelial cells secrete BMP4 in response to hypoxia and promote proliferation and migration of vascular smooth muscle cells in a BMP4-dependent fashion. These findings indicate that BMP4 plays a dominant role in regulating BMP signaling in the hypoxic pulmonary vasculature and suggest that endothelium-derived BMP4 plays a direct, paracrine role in promoting smooth muscle proliferation and remodeling in hypoxic PH.     

低氧条件下共培养体系中肺动脉内皮细胞经Notch1/Jagged1信号通路调控肺动脉平滑肌细胞的增殖

目的探讨低氧条件下细胞共培养体系中肺动脉内皮细胞经由Notch1/Jagged1信号通路调控肺动脉平滑肌细胞的增殖。方法建立Transwell共培养体系,将肺动脉内皮细胞(PAEC)和平滑肌细胞(PASMC)分别接种于下室和上室,PAEC经DAPT(Notch信号阻断剂)或(和)S iR-NA-Jagged1预处理后,与PASMC共同置入自动常压缺氧孵箱进行低氧处理。根据PAEC是否行DAPT、Jagged1小RNA干扰预处理进行实验分组:常氧时PAEC与PASMC共培养对照组(N)、低氧时PAEC与PASMC共培养组(H1)、低氧时DAPT(终浓度10μmol/L)预处理PAEC与PASMC共培养组(H2)、低氧时S iRNA-Jagged1预处理PAEC与PASMC共培养组(H3)、低氧时DAPT加S iRNA-Jagged1预处理PAEC与PASMC共培养组(H4)。用3H-TdR掺入法检测PAEC和PASMC增殖情况,RT-PCR检测PAEC中Notch1、Jagged1 mRNA表达水平。结果低氧时各组PAEC和PASMC的3H-TdR掺入量明显高于常氧共培养对照组(均P<0.01);与H1组比较,...     

Smooth Muscle alpha-actin is a direct target of Notch/CSL

Intercellular signaling mediated by Notch receptors is essential for proper cardiovascular development and homeostasis. Notch regulates cell fate decisions that affect proliferation, survival, and differentiation of endothelial and smooth muscle cells. It has been reported that Jagged1-Notch interactions may participate in endocardial cushion formation by inducing endothelial-to-mesenchymal transformation. Here, we show that Notch directly regulates expression of the mesenchymal and smooth muscle cell marker smooth muscle alpha-actin (SMA) in endothelial and vascular smooth muscle cells via activation of its major effector, CSL. Notch/CSL activation induces SMA expression during endothelial-to-mesenchymal transformation, and Notch activation is required for expression of SMA in vascular smooth muscle cells. CSL directly binds a conserved cis element in the SMA promoter, and this consensus sequence is required for Notch-mediated SMA induction. This is the first evidence of the requirement for Notch activation in the regulation of SMA expression.     

Notch regulation of myogenic versus endothelial fates of cells that migrate from the somite to the limb

Multipotent Pax3-positive (Pax3⁺) cells in the somites give rise to skeletal muscle and to cells of the vasculature. We had previously proposed that this cell-fate choice depends on the equilibrium between Pax3 and Foxc2 expression. In this study, we report that the Notch pathway promotes vascular versus skeletal muscle cell fates. Overactivating the Notch pathway specifically in Pax3⁺ progenitors, via a conditional Pax3^NICD allele, results in an increase of the number of smooth muscle and endothelial cells contributing to the aorta. At limb level, Pax3⁺ cells in the somite give rise to skeletal muscles and to a subpopulation of endothelial cells in blood vessels of the limb. We now demonstrate that in addition to the inhibitory role of Notch signaling on skeletal muscle cell differentiation, the Notch pathway affects the Pax3:Foxc2 balance and promotes the endothelial versus myogenic cell fate, before migration to the limb, in multipotent Pax3⁺ cells in the somite of the mouse embryo.During development, the segmented paraxial mesoderm of the somites gives rise to different mesodermal derivatives. As somites mature, cells delaminate from the dorsal dermomyotome to form the skeletal muscle of the myotome and later trunk muscles, or migrate from the hypaxial dermomyotome into the early limb bud to form limb muscles (1). Vascular progenitors also derive from this part of the dermomyotome. In the chicken embryo, a subpopulation of endothelial cells and myogenic progenitors in the trunk (2) and the limb (3) arise from the same multipotent cells in the somite, as do skeletal muscle and vascular smooth muscle of some blood vessels in the trunk (2). Clonal analysis in the mouse has shown that smooth muscle cells of the dorsal aorta and the myotome have a common origin (4). Dermomyotomal cells are marked by Pax3, which is essential for the migration of myogenic progenitors to sites of skeletal muscle formation, such as to the limb (1). Genetic tracing experiments confirm that some endothelial cells in the mouse limb derive from Pax3⁺ cells in the somite (5).Reciprocal inhibition between Pax3 and Foxc2 in the somite, when perturbed genetically in the mouse embryo, affects vascular versus myogenic cell fate choices (6). Signaling molecules impact the somite, potentially changing the Pax3:Foxc2 equilibrium. In the chicken embryo, manipulation of bone morphogenetic protein signaling showed that it promotes an endothelial cell fate, whereas Notch signaling promotes the formation of vascular smooth muscle at the expense of skeletal muscle (2). However, in another report on the chicken embryo, overactivation of Notch signaling was shown to increase the migration of vascular endothelial cells from the somite to the dorsal aorta (7). Notch signaling is active in the hypaxial region of the chick somite (2) and also in somites and in endothelial cells of blood vessels at embryonic day (E) 9.5 in the mouse embryo (7, 8).To examine the role of Notch signaling in the myogenic versus endothelial fate choice in the mouse embryo, we have targeted one allele of Pax3 with a sequence coding for NICD, the constitutively active intracellular domain of Notch receptor 1. In the trunk of such Notch gain-of-function embryos, both vascular smooth and endothelial cells derived from the somite are increased, whereas myogenesis is diminished. In the limbs, fewer Pax3⁺ cells are present initially, reflecting the promotion of an endothelial versus skeletal muscle cell fate. Somite explant experiments confirm this shift in cell fate, which is accompanied by an increase in Foxc2 expression, whereas when Notch signaling is inhibited, the reverse is observed with a relative increase in myogenic cells. We conclude that the endothelial/myogenic cell fate choice takes place in Pax3⁺ cells in the somite, before their migration to the limbs, and is regulated by the Notch signaling pathway which affects the Pax3:Foxc2 genetic equilibrium.     

Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway

Smooth muscle cell proliferation around small pulmonary vessels is essential to the pathogenesis of pulmonary hypertension. Here we describe a molecular mechanism and animal model for this vascular pathology. Rodents engineered to express angiopoietin 1 (Ang-1) constitutively in the lung develop severe pulmonary hypertension. These animals manifest diffuse medial thickening in small pulmonary vessels, resulting from smooth muscle cell hyperplasia. This pathology is common to all forms of human pulmonary hypertension. We demonstrate that Ang-1 stimulates pulmonary arteriolar endothelial cells through a TIE2 (receptor with tyrosine kinase activity containing IgG-like loops and epidermal growth factor homology domains) pathway to produce and secrete serotonin (5-hydroxytryptamine), a potent smooth muscle mitogen, and find that high levels of serotonin are present both in human and rodent pulmonary hypertensive lung tissue. These results suggest that pulmonary hypertensive vasculopathy occurs through an Ang-1/TIE2/serotonin paracrine pathway and imply that these signaling molecules may be targets for strategies to treat this disease.     

The effects of hypoxia on the cells of the pulmonary vasculature.

Pulmonary hypertension is associated with remodelling of pulmonary vessels. Chronic hypoxia is a common cause of pulmonary hypertension and pulmonary vascular remodelling. Vascular remodelling is characterised largely by fibroblast, smooth muscle and endothelial cell proliferation, which results in lumen obliteration. Chronic hypoxia elicits expression of mitogens, growth factors and cytokines by fibroblasts and endothelial cells, and also the suppression of endothelial nitric oxide synthase. Although hypoxic pulmonary vascular remodelling is associated with medial hypertrophy, many in vitro studies have found that hypoxia does not lead to a direct increase in smooth muscle cell proliferation. This paradox is not well understood and this review aims to examine the various reasons why this might be so. The present authors reviewed data from in vitro studies and also considered whether hypoxia could act on adjacent cells such as fibroblasts and endothelial cells to trigger smooth muscle cell proliferation. It is possible that hypoxia is sensed by fibroblasts, endothelial cells, or both, and relayed to adjacent pulmonary artery smooth muscle cells by intercellular signalling, causing proliferation. The present article reviews the data from in vitro studies of hypoxia on the three cellular components of the pulmonary vascular wall, namely endothelial cells, smooth muscle cells and fibroblasts.