Extracellular ATP: potential regulator of hypoxia-induced vasa vasorum neovascula

细胞外 ATP：缺氧诱导的血管新生血管的潜在调节剂

基本信息

批准号：
7837502
负责人：
Evgenia V Gerasimovskaya
金额：
$ 33.33万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-10 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7837502
关键词：
70-kDa Ribosomal Protein S6 Kinases Actins Address Adenine Nucleotides Animals Appearance Atherosclerosis Biological Models Blood Cells Blood Vessels Cattle Cell Proliferation Cells Chronic Cytoskeleton DNA Sequence Rearrangement Data Development Endothelial Cells Exhibits Exocytosis Fibroblasts GTP-Binding Proteins Goals Growth Guanosine Triphosphate Hypertension Hypoxia In Vitro Inflammatory Knock-out Life Lung Mediating Metabolic Modeling Mole the mammal Molecular Molecular Genetics Neonatal Pathologic Neovascularization Pathway interactions Phenotype Play Principal Investigator Process Pulmonary Circulation Pulmonary Hypertension Pulmonary artery structure Purines Purinoceptor Pyrimidine Nucleotides Recruitment Activity Regulation Research Proposals Role Signal Pathway Signal Transduction Signaling Molecule Stimulus System Systemic disease Techniques Testing Translating Tube Tunica Adventitia Vascular Diseases Vascular Endothelial Growth Factors Vascular remodeling Vascularization Vasculitis Work analog angiogenesis autocrine cell type clinically relevant density extracellular human FRAP1 protein inhibitor/antagonist macrophage migration monocyte neovascularization paracrine progenitor public health relevance pulmonary arterial hypertension purine receptor receptor coupling response restenosis rho shear stress therapeutic target vasa vasorum

项目摘要

DESCRIPTION (provided by applicant): Pathological vascular remodeling is a key component and frequently life-threatening consequence, of vascular diseases in both the systemic and pulmonary circulation. In a neonatal model of hypoxic pulmonary hypertension, we have demonstrated that hypoxia-induced pulmonary artery (PA) remodeling is associated with marked increases in the density of vasa vasorum network. The observed increases in vasa density suggests that neovascularization process may contribute to the progression of pulmonary vascular remodeling and hypertension. The long-term goal of our studies is to evaluate the precise cellular mechanisms and endogenous molecular factors that mediate vasa vasorum neovascularization in hypoxia-induced pulmonary vascular remodeling. Extracellular adenine nucleotides are increasingly recognized as important regulators of vascular functions. Since within the PA adventitial compartment, ATP can be released from a number of vascular and blood cells in response to hypoxia, it could be expected that in the hypoxic vessel microenvironment, extracellular ATP may be the signaling molecules involved in the hypoxia-induced PA adventitial neovascularization. Our preliminary studies in vitro have demonstrated that vasa vasorum endothelial cells (VVEC) isolated from PA adventitia are distinct in their dramatic proliferative responses to extracellular ATP. In turn, hypoxia was found to be a potent inducer of ATP release. Therefore, we hypothesized that extracellular ATP may act as an autocrine/paracrine factor in stimulating hypoxia-induced angiogenic responses in VVEC. Using cultured vasa vasorum endothelial cell as a model system, the specific aims are proposed to (i) determine the angiogenic capacity of extracellular ATP and intracellular signaling pathways that play critical roles in hypoxia- and ATP-induced angiogenic responses in VVEC; (ii) elucidate the intracellular mechanisms through which hypoxia induces ATP release from VVEC; (iii) test the possibility that endogenously released ATP plays an autocrine role in mediating the effects of hypoxia in VVEC. Ultimately, this research proposal aspires to translate fundamental questions of purinergic signaling to the clinically relevant problem of hypoxia-induced angiogenesis. The characterization of an angiogenic phenotype of VVEC, including purinergic receptors and coupled signaling pathways, will provide unique targets for therapeutic strategies aimed at inhibiting pathologic angiogenesis in blood vessel wall. PUBLIC HEALTH RELEVANCE: Pathological vascular remodeling is a key component and frequently life-threatening consequence of vascular diseases in both the systemic and pulmonary circulation. An increasing body of experimental data suggest that vasa vasorum expansion may contribute to hypoxia-induced pulmonary vascular remodeling associated with pulmonary arterial hypertension. Therefore, the long-term goal of our studies is to evaluate the precise cellular mechanisms and endogenous molecular factors that mediate vasa vasorum neovascularization. Specifically, using cultured vasa vasorum endothelial cells (VVEC) isolated from pulmonary adventitia of chronically hypoxic animals, we will test the hypothesis that extracellular ATP may act as an autocrine/paracrine factor in stimulating hypoxia-induced angiogenic responses in VVEC.

描述（由申请人提供）：病理性血管重塑是全身和肺循环血管疾病的关键组成部分，并且常常危及生命。在新生儿缺氧性肺动脉高压模型中，我们证明缺氧诱导的肺动脉（PA）重塑与血管滋养管网络密度的显着增加相关。观察到的血管密度增加表明，新血管形成过程可能有助于肺血管重塑和高血压的进展。我们研究的长期目标是评估缺氧诱导的肺血管重塑中介导血管滋养管新生血管形成的精确细胞机制和内源性分子因素。细胞外腺嘌呤核苷酸越来越被认为是血管功能的重要调节剂。由于在PA外膜室中，许多血管和血细胞响应缺氧而释放ATP，因此可以预期，在缺氧的血管微环境中，细胞外ATP可能是参与缺氧诱导的PA外膜的信号分子。新血管形成。我们的体外初步研究表明，从 PA 外膜分离的血管滋养管内皮细胞 (VVEC) 对细胞外 ATP 具有显着的增殖反应。反过来，缺氧被发现是 ATP 释放的有效诱导剂。因此，我们假设细胞外 ATP 可能作为自分泌/旁分泌因子刺激 VVEC 中缺氧诱导的血管生成反应。使用培养的血管滋养管内皮细胞作为模型系统，提出的具体目标是（i）确定细胞外 ATP 的血管生成能力和细胞内信号通路，它们在 VVEC 中缺氧和 ATP 诱导的血管生成反应中发挥关键作用； (ii) 阐明缺氧诱导 VVEC 释放 ATP 的细胞内机制； (iii) 测试内源释放的 ATP 在介导 VVEC 缺氧影响中发挥自分泌作用的可能性。最终，这项研究计划旨在将嘌呤能信号传导的基本问题转化为缺氧诱导的血管生成的临床相关问题。 VVEC 血管生成表型的表征，包括嘌呤能受体和耦合信号通路，将为旨在抑制血管壁病理性血管生成的治疗策略提供独特的靶点。公共卫生相关性：病理性血管重塑是全身和肺循环血管疾病的关键组成部分，并且经常危及生命。越来越多的实验数据表明，滋养血管扩张可能有助于缺氧诱导的与肺动脉高压相关的肺血管重塑。因此，我们研究的长期目标是评估介导血管滋养管新生血管形成的精确细胞机制和内源性分子因素。具体来说，我们将使用从长期缺氧动物的肺外膜中分离出的培养的血管滋养管内皮细胞（VVEC）来检验细胞外 ATP 可能作为自分泌/旁分泌因子刺激 VVEC 中缺氧诱导的血管生成反应的假设。