内皮祖细胞与低氧性肺动脉高压

低氧性肺动脉高压(HPH)是一种致死性很高的肺血管疾病,其发病与血管内皮的损伤密切相关.近年来研究表明,内皮祖细胞(EPCs)在HPH血管内皮修复中具有重要作用.本文总结了近年来EPCs动员、归巢的分子生物学研究进展.研究了EPCs在HPH发生、发展中的作用,以及药物和EPCs移植对HPH的影响.     

循环内皮祖细胞在肺动脉高压形成中的作用及治疗学应用前景

近年来,内皮祖细胞在肺动脉高压(pulmonary arterial hypertension,PAH)形成中的作用越来越受到学术界重视,基于内皮祖细胞移植治疗PAH的报道也逐年增多.内皮祖细胞存在于骨髓、大动脉血管外膜或循环血液中,在肺动脉内皮损伤的情况下可在损伤部位增殖分化为成熟的内皮细胞,进而通过重建正常的肺血管内皮结构和功能达到治疗PAH的效果.本文对循环内皮祖细胞在PAH形成中的作用及其应用前景作一综述.     

内皮祖细胞和肺动脉高压

肺动脉高压是以肺动脉压和肺血管阻力进行性增加及右心功能衰竭为特征,内皮功能障碍为主的恶性肺血管疾病.本文总结了近年来内皮祖细胞(EPC)动员、归巢分子生物学的研究进展.研究了血管内皮生长因子等生长因子和他汀类等药物对EPC动员,归巢治疗肺动脉高压的影响以及EPC、基因修饰后EPC移植对肺动脉高压治疗的影响.同时讨论了EPC治疗的潜在不良反应.EPC为肺动脉高压患者提供新的治疗方法.     

内皮祖细胞在肺动脉高压治疗中的应用

肺动脉高压一直以来缺乏有效的治疗措施,而近年来基于内皮祖细胞的细胞疗法和基因疗法有望成为肺动脉高压治疗的新理念。本文总结了基于内皮祖细胞的细胞疗法和基因疗法在治疗肺动脉高压中的作用机制,分析了其在治疗肺动脉高压中的不足,并展望其在未来临床治疗肺动脉高压中的应用前景。     

干/祖细胞在肺动脉高压中的研究进展

肺动脉高压是一类病死率极高、严重威胁人类健康的临床综合征，其病理特征以肺动脉内皮细胞损伤为始动因素，平滑肌细胞、成纤维细胞等参与肺血管重塑，最终导致不同程度右心功能衰竭。干/祖细胞具有多向分化潜能，即通过分化成为特定细胞参与肺血管重塑，也可以修复或替换受损肺血管结构，参与肺血管修复。本文对不同类型干/祖细胞在PAH肺血管重塑过程中的作用及以干/祖细胞为基础的PAH细胞移植治疗进行综述。     

内皮祖细胞对血管新生的影响及他汀的干预作用

他汀类药物作为传统降血脂药物,其降脂外作用逐渐受到重视,尤其在保护血管内皮功能促进血管新生方面。血管内皮祖细胞作为血管内皮前体细胞,参与出生后血管新生过程,促进血管内皮修复。本文就他汀类药物对血管内皮祖细胞及血管新生影响的研究进展做一综述     

血管内皮生长因子与慢性阻塞性肺疾病继发肺动脉高压的关系

血管内皮生长因子(vascular endothelial growth factor,VEGF)是一种重要的血管内皮细胞丝裂原和通透因子.肺血管的重塑与慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)继发肺动脉高压密切相关.VEGF贯穿于COPD发展的全过程,在COPD的不同时期呈现不同的表达水平,发挥不同的生物学作用.气道炎症、低氧等因素可以在COPD早期促进VEGF及其受体的表达上调从而导致肺血管重塑的发生发展,VEGF也可以对COPD后期继发肺动脉高压时的重度肺血管重塑起到一定的修复作用.通过阐述VEGF、COPD肺血管重塑及继发肺动脉高压之间的相互关系,可以对COPD继发肺动脉高压的诊断和治疗提供新的思路.     

肺血管内皮功能紊乱与肺动脉高压

肺动脉高压是以肺血管阻力进行性增加并伴有不可逆的血管重塑为特征的疾病.越来越多的研究表明,肺血管内皮功能紊乱在肺动脉高压形成的起始及发展阶段都起着重要作用.本文就肺血管内皮功能紊乱在肺动脉高压发病机制中的研究进展作一综述.     

内皮祖细胞与PI3K/Akt信号传导通路

内皮祖细胞作为内皮的前体细胞,主要来源于骨髓,在成人受损血管的修复、新生血管发生/生成中起重要作用.多种伴有血管内皮细胞损伤的疾病都可引起外周血循环、内皮祖细胞数量、功能的变化.因此,内皮祖细胞功能的研究,日益为人们所关注.研究显示PI3K/Akt信号传导通路在内皮祖细胞的动员、迁移、归巢、分化、抗凋亡上发挥重要作用.现主要就内皮祖细胞与PI3K/Akt信号传导通路关系作一综述.     

内皮祖细胞与血管内狭窄

血管内皮功能不良的一个机制可能是内皮祖细胞相对缺乏，难以修复血管损伤。内膜损伤与血管内狭窄有密切联系，因而内皮祖细胞在修复内膜、防治血管狭窄和支架内再狭窄中的作用倍受关注。     

缺氧对糖尿病血管内皮祖细胞的影响

血管内皮的损害和再生对维持血管的完整性十分重要,血循环中骨髓来源的血管内皮祖细胞有助于血管内皮的修复.局部缺血后,血管内皮祖细胞从骨髓动员到血液中,然后归巢到缺血组织处,在缺血处通过旁分泌生长因子或者渗入血管来促进新生血管形成.糖尿病患者的血管内皮祖细胞在缺氧条件下,功能受到损害,包括动员、附着、迁移、增殖等一系列环节...     

内皮前体细胞及其与肺疾病关系的研究进展

内皮前体细胞存在于骨髓、外周血和脐带血中,可以分化为成熟的内皮细胞.不仅参与胚胎期的血管发育,也在成年的血管新生中起作用.肺部疾病尤其是炎症性疾病,几乎都存在血管内皮的损伤与修复机制.本文就内皮前体细胞的来源、生物学特征和功能,及其在肺疾病中的研究进展进行概述.     

内皮前体细胞及其与肺疾病关系的研究进展

内皮前体细胞存在于骨髓、外周血和脐带血中,可以分化为成熟的内皮细胞.不仅参与胚胎期的血管发育,也在成年的血管新生中起作用.肺部疾病尤其是炎症性疾病,几乎都存在血管内皮的损伤与修复机制.本文就内皮前体细胞的来源、生物学特征和功能,及其在肺疾病中的研究进展进行概述.     

内皮细胞损伤与修复的研究进展

内皮细胞是重要代谢和内分泌器官,在调节血管功能中起重要作用。多种心脑血管疾病(如动脉粥样硬化、高血压、糖尿病血管并发症等)的发生发展与内皮损伤密切相关。然而血管内皮细胞损伤的机制尚未完全明了。大量研究表明,内皮细胞损伤机制主要涉及炎症反应和氧化应激。内皮祖细胞在修复损伤内皮过程中发挥重要作用。多种化学药物和中药,通过减少诱发因素、抑制炎症反应与氧化应激反应、延缓内皮细胞衰老等途径发挥内皮保护作用。     

Vascular progenitor cells in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is commonly associated with vascular changes in the pulmonary and systemic circulations. Pulmonary muscular arteries characteristically show intimal hyperplasia, which is produced in part by the proliferation of poorly differentiated smooth muscle cells. The origin of these cells has not been determined. Bone marrow has the capacity to produce and mobilize progenitor cells that may be recruited at sites of vascular damage and contribute to vascular repair through their differentiation into endothelial cells. Nevertheless, under some circumstances bone marrow-derived progenitor cells may migrate into the intima and differentiate into smooth muscle cells. Local factors and cell-to-cell contact are critical in determining the fate of progenitor cells in the vessel wall. Studies assessing the number of circulating bone marrow-derived vascular progenitor cells indicate that COPD is characterized by a reduction in circulating hemopoietic and vascular progenitors. The mechanisms of this reduction have not been elucidated. It has been suggested that this process may lead to reduced vascular repair capacity and increase the risk of cardiovascular complications, which are associated with significant morbidity and mortality in COPD. Further investigation in this field and elucidation of the underlying mechanisms will contribute to a better management of this major complication of COPD.     

Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: efficacy of combined cell and eNOS gene therapy in established disease

Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance caused by narrowing and loss of pulmonary microvasculature, which in its late stages becomes refractory to traditional therapies. We hypothesized that bone marrow-derived endothelial progenitor cells (EPCs), which normally function to repair and regenerate blood vessels, would restore pulmonary hemodynamics and increase microvascular perfusion in the rat monocrotaline (MCT) model of PAH. Mononuclear cells were isolated from the bone marrow of syngeneic Fisher-344 rats by Ficoll gradient centrifugation and cultured for 7 to 10 days in endothelial growth medium. Fluorescently labeled endothelial-like progenitor cells (ELPCs) engrafted at the level of the distal pulmonary arterioles and incorporated into the endothelial lining in the MCT-injured lung. The administration of ELPCs 3 days after MCT nearly completely prevented the increase in right ventricular systolic pressure seen at 3 weeks with MCT alone (31.5+/-0.95 versus 48+/-3 mm Hg, respectively; P<0.001), whereas injection of skin fibroblasts had no protective effect (50.9+/-5.4 mm Hg). Delayed administration of progenitor cells 3 weeks after MCT prevented the further progression of PAH 2 weeks later (ie, 5 weeks after MCT), whereas only animals receiving ELPCs transduced with human endothelial NO-synthase (eNOS) exhibited significant reversal of established disease at day 35 (31+/-2 mm Hg, P<0.005) compared with day 21 (50+/-3 mm Hg). Fluorescent microangiography revealed widespread occlusion of pulmonary precapillary arterioles 3 weeks after MCT, whereas arteriolar-capillary continuity and microvascular architecture was preserved with the administration of syngeneic ELPCs. Moreover, the delivery of ELPCs to rats with established PAH resulted in marked improvement in survival, which was greatest in the group receiving eNOS-transduced cells. We conclude that bone marrow-derived ELPCs can engraft and repair the MCT-damaged lung, restoring microvasculature structure and function. Therefore, the regeneration of lung vascular endothelium by injection of progenitor cells may represent a novel treatment paradigm for patients with PAH.     

Pro-angiogenic hematopoietic progenitor cells and endothelial colony-forming cells in pathological angiogenesis of bronchial and pulmonary circulation

Dysregulation of angiogenesis is a common feature of many disease processes. Vascular remodeling is believed to depend on the participation of endothelial progenitor cells, but the identification of endothelial progenitors in postnatal neovascularization remains elusive. Current understanding posits a role for circulating pro-angiogenic hematopoietic cells that interact with local endothelial cells to establish an environment that favors angiogenesis in physiologic and pathophysiologic responses. In the lung, increased and dysregulated angiogenesis is a hallmark of diseases of the bronchial and pulmonary circulations, manifested by asthma and pulmonary arterial hypertension (PAH), respectively. In asthma, T_Helper-2 immune cells produce angiogenic factors that mobilize and recruit pro-inflammatory and pro-angiogenic precursors from the bone marrow into the airway wall where they induce angiogenesis and fuel inflammation. In contrast, in PAH, upregulation of hypoxia-inducible factor (HIF) in vascular cells leads to the production of bone marrow-mobilizing factors that recruit pro-angiogenic progenitor cells to the pulmonary circulation where they contribute to angiogenic remodeling of the vessel wall. This review focuses on current knowledge of pro-angiogenic progenitor cells in the pathogenesis of asthma and PAH.     

Resident vascular progenitor cells

Homeostasis of the vessel wall is essential for maintaining its function, including blood pressure and patency of the lumen. In physiological conditions, the turnover rate of vascular cells, i.e. endothelial and smooth muscle cells, is low, but markedly increased in diseased situations, e.g. vascular injury after angioplasty. It is believed that mature vascular cells have an ability to proliferate to replace lost cells normally. On the other hand, recent evidence indicates stem/progenitor cells may participate in vascular repair and the formation of neointimal lesions in severely damaged vessels. It was found that all three layers of the vessels, the intima, media and adventitia, contain resident progenitor cells, including endothelial progenitor cells, mesenchymal stromal cells, Sca-1+ and CD34+ cells. Data also demonstrated that these resident progenitor cells could differentiate into a variety of cell types in response to different culture conditions. However, collective data were obtained mostly from in vitro culture assays and phenotypic marker studies. There are many unanswered questions concerning the mechanism of cell differentiation and the functional role of these cells in vascular repair and the pathogenesis of vascular disease. In the present review, we aim to summarize the data showing the presence of the resident progenitor cells, to highlight possible signal pathways orchestrating cell differentiation toward endothelial and smooth muscle cells, and to discuss the data limitations, challenges and controversial issues related to the role of progenitors. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited".     

Impaired apoptosis of pulmonary endothelial cells is associated with intimal proliferation and irreversibility of pulmonary hypertension in congenital heart disease.

OBJECTIVES: This study sought to assess the cellular and histologic basis of irreversible pulmonary hypertension (PHT) in the clinical setting of congenital heart disease (CHD). BACKGROUND: Although many children with CHD develop pulmonary vascular disease, it is unclear why this complication is reversible after complete repair in some cases but irreversible in others. Because failure of endothelial cell apoptosis might lead to intimal proliferation and lack of reversibility of PHT, we investigated this and other key markers of vasoactivity and angiogenesis in subjects with PHT and CHD. METHODS: We assessed antiapoptotic and proapoptotic markers in vascular and perivascular cells in lung biopsy samples from 18 patients with CHD, 7 with reversible and 11 with irreversible PHT, and 6 control patients. Immunostaining for endothelial nitric oxide synthase, vascular endothelial growth factor, and CD34 (markers of vasoactivity and neoangiogenesis) was also performed. RESULTS: The antiapoptotic protein Bcl-2 was highly expressed by pulmonary endothelial cells in all cases of irreversible PHT but in no cases of reversible PHT, nor in control patients (p < 0.001). Intimal proliferation was present in 10 of 11 irreversible PHT cases, but never observed in reversible PHT (p < 0.001). Similarly, perivascular inflammatory T-cells expressed more antiapoptotic proteins in irreversible PHT (p < 0.01). Irreversible PHT cases were also more likely to show compensatory upregulation of vascular endothelial growth factor and new small vessel formation at the sites of native vessel stenosis or occlusion (p < 0.001). CONCLUSIONS: Irreversible PHT is strongly associated with impaired endothelial cell apoptosis and antiapoptotic signaling from perivascular inflammatory cells. These changes are associated with intimal proliferation and vessel narrowing, and thereby may contribute to clinical outcomes associated with pulmonary hypertension.     

Vascular smooth muscle progenitor cells: building and repairing blood vessels

Molecular pathways that control the specification, migration, and number of available smooth muscle progenitor cells play key roles in determining blood vessel size and structure, capacity for tissue repair, and progression of age-related disorders. Defects in these pathways produce malformations of developing blood vessels, depletion of smooth muscle progenitor cell pools for vessel wall maintenance and repair, and aberrant activation of alternative differentiation pathways in vascular disease. A better understanding of the molecular mechanisms that uniquely specify and maintain vascular smooth muscle cell precursors is essential if we are to use advances in stem and progenitor cell biology and somatic cell reprogramming for applications directed to the vessel wall.