Crosstalk Between Inflammation and Angiogenesis

炎症和血管生成之间的串扰

基本信息

批准号：
8175339
负责人：
Triantafyllos Chavakis
金额：
$ 23.82万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8175339
关键词：
Adhesives Affect Angiogenic Factor Anti-Inflammatory Agents Anti-inflammatory Antibodies Biological Assay Blood Vessels Cell Proliferation Cell Survival Cell physiology Cells Cellular Structures Complement DNA Repair Development Disease Endothelial Cells Extracellular Matrix Growth Factor Hypoxia Hypoxia Inducible Factor In Vitro Inflammation Inflammatory Inflammatory Response Ischemia Limb structure Link Maintenance Malignant Neoplasms Modeling Mus Natural Immunity Organ Pathologic Pathologic Neovascularization Pericytes Phenotype Phosphorylation Proliferating Retina Retinal Diseases Retinopathy of Prematurity Role Tumor Angiogenesis Vascular Endothelial Growth Factor Receptor Wound Healing angiogenesis cell motility complement C3 precursor complement system human H2AX protein in vivo inhibitor/antagonist macrophage matrigel neovascularization new growth receptor response tumor tumor growth

项目摘要

Angiogenesis, the growth of new blood vessels, is important for organ development, wound healing and various pathological conditions such as tumor growth or proliferative retinopathies. Neovascularization depends on endothelial cell survival/proliferation, adhesive contacts of the endothelial cells with the extracellular matrix and with pericytes, on endothelial cell migration and sprouting, as well as on the function of growth factors. There is emerging evidence that inflammatory cells and components of the innate immunity regulate endothelial cell functions related to angiogenesis. 1) The complement system is a major component of the innate immunity. How complement may regulate angiogenesis is not clear. The participation of the complement system in hypoxia-driven retina angiogenesis was investigated by using complement components and inhibitors and genetically modified mice that lack the central complement component C3, as well as the receptors C3aR and C5aR. In particular, we found that C3-deficient mice had higher neovascularization in the model of retinopathy of prematurity (ROP) and in the in vivo Matrigel plug assay. Moreover, antibody blockade of C5, treatment with C5aR antagonist, or C5aR-deficiency in mice was associated with increased pathologic retina angiogenesis. While complement did not directly affect angiogenesis-related endothelial cell functions, we found that complement regulated the polarization of macrophages to a pro-inflammatory, anti-angiogenic macrophage phenotype that also secreted high levels of soluble VEGF receptor-1. Consistently, macrophage depletion in vivo reversed the increased neovascularization associated with C3- or C5aR-deficiency. We are currently assessing the role of complement for tumor angiogenesis. 2) Hypoxia induces replication arrest in cells, nevertheless, in hypoxia-induced angiogenesis, such as during proliferative retinopathies, endothelial cells need to actively proliferate due to the presence of hypoxia-inducible factors. To understand this we studied the DNA repair response to hypoxia in endothelial cells, including the phosphorylation of histone H2AX. In vitro and in vivo studies revealed that H2AX and the DNA repair response due to hypoxia help endothelial cells overcome the hypoxia-induced replication arrest, thus allowing for maintenance of endothelial cell proliferation under hypoxic conditions and thereby promoting hypoxia-driven angiogenesis. Consistently, H2AX-deficiency or endothelial-specific H2AX-deficiency resulted in reduced hypoxia-driven angiogenesis in the model of retinopathy of prematurity, in hind limb ischemia or in tumor angiogenesis.

血管生成是新血管的生长，对于器官发育，伤口愈合和各种病理状况（例如肿瘤生长或增殖性视网膜病）至关重要。新血管化取决于内皮细胞的存活/增殖，内皮细胞与细胞外基质和周细胞，内皮细胞迁移和发芽以及生长因子的功能。有新的证据表明，炎症细胞和先天免疫的成分调节与血管生成有关的内皮细胞功能。 1）补体系统是先天免疫的主要组成部分。补体如何调节血管生成尚不清楚。补体系统参与缺乏缺乏中央补体成分C3以及受体C3AR和C5AR的补体成分和抑制剂和转基因的小鼠，研究了缺氧驱动的视网膜血管生成。特别是，我们发现C3缺陷型小鼠在预性早产模型（ROP）和体内Matrigel插头测定中具有较高的新血管化。此外，在小鼠中对C5的抗体阻断，用C5AR拮抗剂治疗或C5AR缺陷与病理视网膜血管生成增加有关。虽然补体没有直接影响与血管生成相关的内皮细胞功能，但我们发现补体调节巨噬细胞对促炎性的抗血管生成巨噬细胞表型的极化，该表型也分泌了高水平的可溶性VEGF受体1。一致地，体内巨噬细胞的耗竭逆转了与C3-或C5AR缺陷相关的新血管化。我们目前正在评估补体对肿瘤血管生成的作用。 2）缺氧会诱导细胞中的复制停滞，然而，缺氧诱导的血管生成，例如在增殖性视网膜病变期间，由于存在缺氧诱导因素，内皮细胞需要积极增殖。为了理解这一点，我们研究了内皮细胞中缺氧的DNA修复反应，包括组蛋白H2AX的磷酸化。体外和体内研究表明，缺氧引起的H2AX和DNA修复反应有助于内皮细胞克服缺氧诱导的复制停滞，从而可以在缺氧条件下维持内皮细胞增殖，从而促进缺氧驱动的血管生成。一致地，H2AX缺乏或内皮特异性的H2AX缺陷导致低氧驱动的血管生成降低了预性早产模型，后肢缺血或肿瘤血管生成。