AlphaVbetaIII Activation in Blood and Endothelial Cells in Angiogenesis

血管生成过程中血液和内皮细胞中的 AlphaVbetaIII 激活

• 批准号: 8378029
• 负责人: Tatiana V Byzova
• 金额: $ 32.73万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-15 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8378029
• 关键词: Active Sites; Adhesions; Adult; Agonist; Biological Assay; Biology; Blood; Blood Cells; Blood Platelets; Blood Vessels; Blood capillaries; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; CXCR4 gene; Cell Adhesion; Cells; Cellular biology; Chimera organism; Complex; Endothelial Cells; Endothelium; Event; Growth; Imagery; Immune; In Vitro; Injection of therapeutic agent; Injury; Integrin beta3; Integrins; Ischemia; Knock-in Mouse; Knock-out; Knockout Mice; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Organism; Pathologic Neovascularization; Pathology; Phosphorylation; Play; Process; Receptor Signaling; Recovery; Recruitment Activity; Regulation; Role; Stromal Cell-Derived Factor 1; Structure; Testing; Tissues; Transgenic Organisms; Tyrosine Phosphorylation; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Virus; Wild Type Mouse; Wound Healing; angiogenesis; capillary; cell type; in vivo; in vivo Model; migration; mouse model; mutant; neovascularization; novel; novel therapeutics; operation; receptor; response; tissue repair; tumor; tumor growth; wound

The B3 subfamily of integrins are two-way signaling receptors that play essential roles in cell biology. Their influences on platelet function and vascular biology are particularly prominent. aVB3 receptor serves as a crucial regulation of angiogenesis, the process of blood vessel growth in adult organism which underlies a number of pathologies, including ischemic injury, cancer and tissue repair. Recent studies demonstrated that angiogenesis is a systemic process where vascular cells coordinate actions with immune cells of blood and tissue origin, and circulating blood components. Using a variety of in vivo models we have shown that activation of aVB3 occurs on endothelium at the sites of active angiogenesis and appears to control several angiogenesis-dependent responses including recovery after ischemia, tumor growth and wound healing. Using a knockin mouse model expressing mutant form of B3 unable to undergo phosphorylation, we demonstrated that B3 phosphorylation is essential for neovascularization in vivo. However, abnormal angiogenesis in B3 knockin mice was completely reversed by bone marrow transplantation was and appear to be dictated primarily by B3 integrin on bone marrow derived (BMDC) cells. Many of these recruited cells express CXCR4, a receptor for SDF-1. Moreover, SDF-1 treatment of BMDC seems to modulate cell adhesion via (33 integrin. These studies identified a novel and unconventional function of B3 integrin in angiogenesis and emphasizes that the process of angiogenesis involve co-operation of numerous cell types and tissues. The overall hypothesis to be tested is that aVB3 activation and phosphorylation are essential for in vivo cooperation between blood, bone marrow-derived and endothelial cells. The following Specific Aims are proposed to test our hypothesis: Aim I. To assess the role of p3 integrin activation and phosphorylation on the interactions between endothelial, bone marrow derived cells and platelets during angiogenesis in vivo. Double transgenic lines, DiYF-GFP and p3-/- GFP mice will be utilized for visualization of BMDC in bone marrow chimeras. We will also determine the role of platelet B3 on angiogenesis and recruitment of BMDC. Aim II. To assess the molecular and cellular mechanisms controlling interaction between circulating blood cells and endothelium and determine the role of p3 integrin in this process. Endothelial and BMDC cells from WT, B3-/- and B3 knockin mice as well as cells characterized by impaired integrin activation (from Project 1 and 2) will be used. Aim III. To assess the role of integrin activation in the process of p3 integrindependent adhesion of BMDC to endothelium. We will determine the role of SDF-1/CXCR4 axis in integrinmediated responses. These studies will delineate the cellular and molecular mechanisms of angiogenesis and result in identification of novel therapeutic strategies to treat ischemia, wound and other pathologies.

整联蛋白的B3亚家族是双向信号受体，在细胞生物学中起重要作用。它们对血小板功能和血管生物学的影响特别突出。 AVB3受体是对血管生成的关键调节，这是成人生物体血管生长的过程，这些过程是许多病理基础的，包括缺血性损伤，癌症和组织修复。最近的研究表明，血管生成是一个系统的过程，其中血管细胞与血液和组织起源的免疫细胞以及循环血成分进行了协调作用。使用多种体内模型，我们已经表明，AVB3的激活发生在活性血管生成部位的内皮上，并且似乎控制了几种依赖血管生成的反应，包括缺血后的恢复，肿瘤生长和伤口愈合。使用敲击鼠标模型 表达B3突变形式无法进行磷酸化，我们证明了B3磷酸化对于体内的新血管化至关重要。然而，骨髓移植完全逆转了B3敲击蛋白小鼠的异常血管生成，并且似乎主要由B3整合素在衍生的骨髓（BMDC）细胞上决定。这些招募的细胞中有许多表达CXCR4，一种用于SDF-1的受体。此外，BMDC的SDF-1处理似乎通过（33整合素。这些研究确定了B3整合素在血管生成中的新颖且非常规的功能，并强调血管生成的过程涉及许多细胞类型和组织的合作。 磷酸化对于血液，骨髓来源和内皮细胞之间的体内合作至关重要。 提出了以下特定目的来检验我们的假设：目标I。评估P3整合素激活和磷酸化对体内血管生成期间内皮，骨髓衍生细胞和血小板之间相互作用的作用。双转基因线，DIYF-GFP和P3 - / - GFP小鼠将用于在骨髓嵌合体中可视化BMDC。我们还将确定血小板B3在BMDC的血管生成和募集中的作用。目标II。评估控制循环血细胞和内皮之间相互作用的分子和细胞机制，并确定P3整联蛋白在此过程中的作用。将使用来自WT，B3 - / - 和B3敲击蛋白小鼠的内皮和BMDC细胞以及以整联蛋白活化受损（来自项目1和2）为特征的细胞。目标三。评估整联蛋白激活在P3整合独立过程中的作用 BMDC对内皮的粘附。我们将确定SDF-1/CXCR4轴在整合介导的响应中的作用。这些研究将描述血管生成的细胞和分子机制，并确定治疗缺血，伤口和其他病理学的新型治疗策略。