Annexin 2 in Angiogenesis

膜联蛋白 2 在血管生成中的作用

• 批准号: 8098802
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8098802
• 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; CD11 Antigens; 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; Platelet-Derived Growth Factor; 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; Vascular Endothelial Growth Factor Receptor-1; 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（由申请人提供）：虽然对于从血管闭塞事件（如心肌梗死、卒中和外周血管功能不全）中恢复至关重要，但新生血管发育也是良性和恶性肿瘤生长和进展的基础。在这个建议中，我们假设，纤溶受体复合物，被称为膜联蛋白2/p11系统，通过支持在血管细胞及其前体的表面的关键蛋白酶活性的发展，促进新血管生成。具体来说，我们计划集中在膜联蛋白2（A2）的作用，招募和分化的血管壁细胞的稳定发展中的新血管。A2属于钙调节磷脂结合蛋白的60个成员家族，在整个系统发育树中表达。我们和其他人已经确定A2作为主要的内皮细胞纤维蛋白溶解受体，结合组织纤溶酶原激活剂及其生理底物，纤溶酶原。这种组装大大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，小鼠完全缺乏A2有显着受损的新血管生成。新的初步数据证实并扩展了这些发现，证明了A2基因敲除小鼠的肿瘤移植物生长失败是由于肿瘤血管生成受损。我们特别注意到缺乏新生血管，新生血管扩张和壁细胞缺乏。携带肿瘤的A2缺失小鼠显示出减少的循环骨髓来源的VEGFR 1 +/CD 11+造血前体，并且在移植A2+/+骨髓的A2-/-小鼠后肿瘤生长可以恢复。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生血管生成是必不可少的。我们的目的是[1]确定A2是否通过促进壁细胞的募集来支持新血管的稳定[2]确定PDGF-BB是否通过刺激A2/p11复合物易位到壁细胞前体的表面来招募壁细胞到发育中的新血管，[3]确定A2支持的血管生成是否也需要其辅因子p11的参与，[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而损害血管生成反应。预计这些研究得出的新见解可能会为新生血管疾病的诊断和治疗带来新的模式。