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：
7524143
负责人：
Evgenia V Gerasimovskaya
金额：
$ 38.12万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-10 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7524143
关键词：
70-kDa Ribosomal Protein S6 Kinases Actins Address Adenine Nucleotides Animals Appearance Atherosclerosis Biological Models Blood Cells Blood Vessels Bos taurus Cattle Cell Proliferation Cells Chronic Condition 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 Melanocytic nevus Metabolic Modeling Mole the mammal Molecular Molecular Genetics Neonatal Numbers Pathologic Neovascularization Pathway interactions Phenotype Play Principal Investigator Process Public Health Pulmonary Circulation Pulmonary Hypertension Pulmonary artery structure Purines 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 pulmonary arterial hypertension purine receptor receptor coupling response restenosis rho shear stress size 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）：病理血管重塑是全身性和肺部循环中血管疾病的关键组成部分，并且经常威胁生命的结果。在低氧肺动脉高压的新生儿模型中，我们证明了缺氧诱导的肺动脉（PA）重塑与Vasa vasorum网络密度显着增加有关。观察到的VASA密度增加表明，新血管化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介导缺氧引起的肺血管重塑的精确细胞机制和内源性分子因子。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外来室内，可以从多个血管和血细胞中释放出ATP，以应对缺氧，可以预期，在缺氧血管微环境中，细胞外ATP可能是低氧诱导的PA诱发的信号分子新血管形成。我们在体外的初步研究表明，从PA Adventitia分离出的Vasa vasorum内皮细胞（VVEC）在其对细胞外ATP的急剧增殖反应中与众不同。反过来，发现缺氧是ATP释放的有效诱导剂。因此，我们假设细胞外ATP可以在VVEC中刺激缺氧诱导的血管生成反应时充当自分泌/旁分泌因子。将培养的Vasa vasorum内皮细胞作为模型系统，提出了特定的目的，以（i）确定细胞外ATP和细胞内信号通路的血管生成能力，在VVEC中，在低氧和ATP诱导的血管生成反应中起着关键作用；（ii）阐明缺氧从VVEC释放ATP的细胞内机制；（iii）测试内源性释放ATP的可能性在介导缺氧在VVEC中的影响中起着自分泌作用。最终，该研究提案渴望将嘌呤能信号传导的基本问题转化为缺氧引起的血管生成的临床相关问题。 VVEC的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中病理血管生成的治疗策略提供独特的靶标。公共卫生相关性：病理血管重塑是系统性和肺部循环中血管疾病的关键组成部分，并且经常威胁生命。越来越多的实验数据表明，VASA血管膨胀可能导致缺氧引起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VASA血管血管新血管形成的精确细胞机制和内源性分子因子。具体而言，使用从慢性低氧动物的肺部外膜中分离出的培养的瓦萨血管内皮细胞（VVEC），我们将检验以下假设：细胞外ATP可能在刺激缺氧诱导的VVEC中刺激缺氧诱导的血管疾病反应时充当自身分泌/旁分泌因子。