Annexin 2 in Angiogenesis

膜联蛋白 2 在血管生成中的作用

• 批准号: 7906827
• 负责人: KATHERINE AMBERSON HAJJAR
• 金额: $ 42.25万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7906827
• 关键词: Acute Promyelocytic Leukemia; Allografting; Alteplase; Animal Model; Annexins; Antibodies; Antiphospholipid Syndrome; Attenuated; Benign; Binding; Binding Proteins; Blood Vessels; Blood capillaries; Bone Marrow; Calcium; Cell surface; Cells; Complex; Cornea; Data; Defect; Development; Diagnosis; Dilatation - action; Disease; Endothelial Cells; Event; Failure; Family member; Fibrin; Gelatinase B; Generations; Growth; Health; Hematopoietic; Hemorrhage; Human; Hyperhomocysteinemia; Implant; Knockout Mice; Lead; Malignant Neoplasms; Marrow; Matrix Metalloproteinases; Mediating; Modality; Modeling; Mus; Myocardial Infarction; Neoplasm Metastasis; Oxygen; Peptide Hydrolases; Pericytes; Peripheral; Phospholipids; Phylogenetic Analysis; Physiological; Plasmin; Plasminogen; Population; Recovery; Recruitment Activity; Retinal Diseases; Role; Site; Smooth Muscle Myocytes; Stem cells; Stroke; Supporting Cell; Surface; System; Testing; Thrombosis; Tissues; Transplantation; Trees; Tumor Angiogenesis; Vascular Diseases; Vascularization; angiogenesis; base; capillary; cofactor; collagenase 3; in vivo Model; insight; matrigel; neoplastic; neovascular; novel; overexpression; platelet-derived growth factor BB; postnatal; precursor cell; progenitor; receptor; receptor binding; response; tumor; tumor growth

DESCRIPTION (provided by applicant): While fundamental to recovery from vascular occlusive events such as myocardial infarction, stroke, and peripheral vascular insufficiency, neovascular development also underlies the growth and progression of both benign and malignant tumors. In this proposal, we postulate that that the fibrinolytic receptor complex, known as the annexin 2/p11 system, promotes neoangiogenesis by supporting the development of key protease activities at the surface of vascular cells and their precursors. Specifically, we plan to focus on the role of annexin 2 (A2) in the recruitment and differentiation of vascular mural cells for stabilization of the developing neovessel. A2 belongs to a 60-member family of calcium-regulated, phospholipid-binding proteins expressed throughout the phylogenetic tree. We and others have identified A2 as the major endothelial cell fibrinolytic receptor that binds tissue plasminogen activator and its physiologic substrate, plasminogen. This assembly greatly accelerates plasmin generation, and promotes the dissolution of fibrin. Recently, we demonstrated that mice completely deficient in A2 have markedly impaired neoangiogenesis. New preliminary data substantiate and extend these findings by demonstrating a failure of tumor allograft growth in A2-null mice due to impaired tumor angiogenesis. We note specifically a paucity of neovessels, neovascular dilatation, and a deficiency of mural cells. Tumor-bearing A2-null mice display reduced circulating bone marrow derived VEGFR1+/CD11+ hematopoietic precursors, and tumor growth can be restored upon transplantation of A2-/- mice with A2+/+ marrow. We, therefore, hypothesize that expression of A2 on the surface of vascular cells and vascular precursor cells is essential for effective neoangiogenesis. Our aims are to [1] determine whether A2 supports stabilization of new blood vessels by promoting recruitment of mural cells (pericytes and smooth muscle cells) to sites of angiogenesis in tumor-bearing mice and in humans with cancer, [2] determine whether PDGF-BB recruits mural cells to developing neovessels by stimulating translocation of the A2/p11 complex to the surface of mural cell precursors, [3] determine whether A2-supported angiogenesis also requires participation of its cofactor, p11, and [4] determine whether hyperhomocysteinemia impairs the angiogenic response by derivatizing A2 and blocking its protease-inducing activity. It is anticipated that new insights derived from these studies may lead to novel modalities in the diagnosis and treatment of neovascular disorders.

描述(申请人提供)：虽然血管闭塞事件，如心肌梗死、中风和外周血管功能不全的恢复是基本的，但新血管的发展也是良性肿瘤和恶性肿瘤生长和发展的基础。在这项提议中，我们假设纤溶受体复合体，即膜联蛋白2/p11系统，通过支持血管细胞及其前体表面关键蛋白酶活性的发展来促进新生血管生成。具体地说，我们计划集中在膜联蛋白2(A2)在血管壁细胞的招募和分化中的作用，以稳定正在发育的新生血管。A2属于一个由60个成员组成的钙调节磷脂结合蛋白家族，表达于整个系统发育树中。我们和其他人已经确定A2是主要的内皮细胞纤溶受体，它结合了组织纤溶酶原激活剂及其生理底物纤溶酶原。这种组装极大地加速了纤溶酶的产生，并促进了纤维蛋白的溶解。最近，我们证明了完全缺乏A2的小鼠显著地损害了新生血管的生成。新的初步数据证实并扩展了这些发现，证明了由于肿瘤血管生成受损，A2基因缺失小鼠的肿瘤同种异体生长失败。我们特别注意到新生血管稀少、新生血管扩张和壁细胞缺乏。荷瘤A2缺失小鼠外周血中的VEGFR1+/CD11+造血祖细胞减少，移植A2+/+骨髓的A2-/-小鼠可恢复肿瘤生长。因此，我们假设A2在血管细胞和血管前体细胞表面的表达对于有效的新血管生成是必不可少的。我们的目标是[1]确定A2是否通过促进荷瘤小鼠和癌症患者的血管生成部位招募壁细胞(周细胞和平滑肌细胞)来支持新血管的稳定，[2]确定PDGF-BB是否通过刺激A2/p11复合体到壁细胞前体表面的移位来招募壁细胞以形成新生血管，[3]确定A2支持的血管生成是否还需要其辅因子p11的参与，以及[4]确定高同型半胱氨酸血症是否通过衍生A2并阻断其蛋白酶诱导活性来损害血管生成反应。预计从这些研究中获得的新见解可能导致新血管疾病的诊断和治疗的新模式。