Mechanisms by which MAGP-2 Promotes Angiogenesis

MAGP-2 促进血管生成的机制

• 批准号: 8065215
• 负责人: Allan R Albig
• 金额: $ 0.8万
• 依托单位: INDIANA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8065215
• 关键词: Address; Blood Vessels; Cause of Death; Chemicals; Communication; Cytoplasmic Granules; Development; Endothelial Cells; Event; Exocytosis; Gene Expression Profile; Growth; Health; Human; In Vitro; Infiltration; Integrins; Investigation; Learning; Ligands; Malignant Neoplasms; Medical; Molecular; Neoplasm Metastasis; Play; Proteins; Role; Signal Transduction; Solid Neoplasm; Stimulus; System; Therapeutic; Therapeutic Intervention; United States; Vascular Endothelial Cell; Vascular remodeling; Weibel-Palade Bodies; angiogenesis; antiangiogenesis therapy; base; cell type; combat; human disease; human microfibrillar-associated protein 2; in vitro activity; in vivo; inhibitor/antagonist; notch protein; public health relevance; receptor; response; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Angiogenesis is required for the growth and metastasis of cancers. One of the critical events that occurs during tumor formation, is the remodeling of the angiostatic vascular microenvironment to a pro-angiogenic microenvironment. This remodeling is essential to provide the proper communications between vascular endothelial cells (ECs) and the vascular microenvironment that is critical for proper angiogenesis. Therefore, therapeutic interventions that disrupt communications between ECs and their microenvironment represents a potential approach for inhibiting angiogenesis and cancer. Unfortunately, there remains a great deal to learn about the microenvironment molecules that regulate angiogenesis and the molecular mechanisms by which these molecules functions. To address this problem, we recently conducted a microarray based transcriptome analysis of ECs undergoing angiogenesis in vitro. We identified 39 secreted proteins that were not previously associated with angiogenesis and characterized the angiogenic activity of several of these proteins. In particular, MAGP-2 expression was increased in activated ECs and was found to promote angiogenic activities in vitro and angiogenesis in vivo. We concluded that activated ECs secrete MAGP-2 into the vascular microenvironment to promote angiogenesis. These investigations however did not address the molecular mechanism(s) by which MAGP-2 promotes angiogenesis. Our preliminary results now demonstrate that MAGP-2 promotes angiogenesis by blocking Notch signaling in endothelial cells. Paradoxically, we also find that MAGP-2 promotes Notch signaling in non-endothelial cell types. Simultaneously, we have also found that MAGP-2 is specifically localized to endothelial cytoplasmic granules. Based on these key observations, we hypothesize that MAGP-2 promotes angiogenesis by interfering with EC specific angiostatic Notch receptor/ligand interactions, and that MAGP-2 is secreted from EC granules in response to specific pro-angiogenic chemical stimuli. We will address this hypothesis with three specific aims. Specific aim 1 will take advantage of our observations that MAGP-2 inhibits Notch signaling in ECs but promotes Notch signaling in other cell types. Using this system, we will identify which Notch receptors and ligands are expressed by these cell types, characterize how MAGP-2 interacts with these receptors, ligands, and receptor/ligand pairs, and finally examine the angiogenic consequences of MAGP-2 interaction with various Notch receptor/ligand pairs. In specific aim 2, we will first determine if MAGP-2 is stored in the common EC specific storage granules (Weibel-Palade bodies) or alternative storage granules. We will then proceed to identify MAGP-2 sequences that are necessary to direct granule storage, and the chemical signals that stimulate MAGP-2 exocytosis from ECs. By investigating these molecular mechanisms by which MAGP-2 may promote angiogenesis, we will learn valuable information about how remodeling of vascular microenvironments contributes to angiogenesis and tumorigenesis. Since the development of Notch and integrin inhibitors are currently being developed as anti-angiogenesis therapeutics, and regulated EC exocytosis is hypothesized to play an important role during tumorigenesis, these investigations will make direct contributions to understanding human health and how we treat human disease. PUBLIC HEALTH RELEVANCE: Cancer continues to be a leading cause of death and suffering in the United States. Since all solid tumors depend on angiogenesis (i.e., infiltration of new blood vessels) strategies to block it may provide therapeutic opportunities to treat cancer. To address this medical need, this proposal seeks to characterize new molecules and mechanisms by which angiogenesis is controlled so that we can one day use this information to block angiogenesis and combat cancer.

描述(申请人提供)：肿瘤的生长和转移需要血管生成。在肿瘤形成过程中发生的关键事件之一是血管抑制微环境向促血管生成微环境的重塑。这种重塑对于提供血管内皮细胞(ECs)和血管微环境之间的适当通信是至关重要的，而微环境对正常的血管生成至关重要。因此，干扰内皮细胞与其微环境之间的通讯的治疗性干预是抑制血管生成和癌症的潜在方法。不幸的是，关于调节血管生成的微环境分子以及这些分子发挥作用的分子机制，还有很多需要了解。为了解决这个问题，我们最近对体外血管生成的内皮细胞进行了基于微阵列的转录组分析。我们鉴定了39种以前与血管生成无关的分泌蛋白，并对其中几种蛋白的血管生成活性进行了表征。特别是，MAGP-2在激活的内皮细胞中表达增加，并被发现在体外促进血管生成活性，在体内促进血管生成。我们认为，激活的内皮细胞分泌MAGP-2进入血管微环境，促进血管生成。然而，这些研究并没有涉及MAGP-2促进血管生成的分子机制(S)。我们的初步结果表明，MAGP-2通过阻断内皮细胞中的Notch信号来促进血管生成。矛盾的是，我们还发现MAGP-2促进非内皮细胞类型的Notch信号转导。同时，我们还发现MAGP-2特异性地定位于内皮细胞胞浆颗粒。基于这些关键的观察结果，我们假设MAGP-2通过干扰EC特异性的血管抑制性Notch受体/配体相互作用来促进血管生成，并且MAGP-2是EC颗粒对特定的促血管生成化学刺激的反应而分泌的。我们将以三个具体目标来解决这一假设。具体目标1将利用我们的观察结果，即MAGP-2抑制内皮细胞中的Notch信号，但促进其他类型细胞中的Notch信号。利用这个系统，我们将确定这些细胞类型表达哪些Notch受体和配体，表征MAGP-2如何与这些受体、配体和受体/配体对相互作用，最后检查MAGP-2与各种Notch受体/配体对相互作用的血管生成结果。在具体目标2中，我们将首先确定MAGP-2是存储在共同的EC特异性存储颗粒(Webel-Palade小体)中还是存储在替代存储颗粒中。然后，我们将继续鉴定直接储存颗粒所必需的MAGP-2序列，以及刺激内皮细胞分泌MAGP-2的化学信号。通过研究MAGP-2促进血管生成的分子机制，我们将了解血管微环境重塑如何在血管生成和肿瘤发生中起到重要作用。由于Notch和整合素抑制剂的开发目前正被开发为抗血管生成的治疗药物，并且推测调控的EC胞吐在肿瘤发生过程中发挥重要作用，这些研究将直接有助于了解人类健康和如何治疗人类疾病。与公共卫生相关：在美国，癌症仍然是导致死亡和痛苦的主要原因。由于所有实体肿瘤都依赖于血管生成(即新血管的渗透)，因此阻断它的策略可能会提供治疗癌症的机会。为了满足这一医学需求，这项建议试图描述控制血管生成的新分子和机制，以便我们有一天可以利用这些信息来阻止血管生成和抗击癌症。