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

• 批准号: 7881504
• 负责人: Evgenia V Gerasimovskaya
• 金额: $ 38.25万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 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/7881504
• 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

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）：病理性血管重构是体循环和肺循环血管疾病的关键组成部分，经常危及生命。在新生儿缺氧肺动脉高压模型中，我们证明了缺氧诱导的肺动脉（PA）重塑与血管血管网络密度的显著增加有关。观察到的血管密度增加提示新生血管的形成过程可能有助于肺血管重构和高血压的进展。我们研究的长期目标是评估在缺氧诱导的肺血管重构中介导血管新生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因子。由于在PA外膜室内，许多血管细胞和血细胞在缺氧的情况下会释放ATP，因此可以预期，在缺氧血管微环境中，细胞外ATP可能是参与缺氧诱导的PA外膜新生血管的信号分子。我们的初步体外研究表明，从PA外膜分离的血管内皮细胞（VVEC）对细胞外ATP具有显著的增殖反应。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/旁分泌因子刺激低氧诱导的VVEC血管生成反应。以培养的血管内皮细胞为模型系统，提出了具体的目标：(i)确定细胞外ATP和细胞内信号通路的血管生成能力，这些信号通路在缺氧和ATP诱导的VVEC血管生成反应中起关键作用；（ii）阐明缺氧诱导VVEC释放ATP的细胞内机制；（iii）检验内源性释放ATP在介导VVEC缺氧作用中发挥自分泌作用的可能性。最终，本研究计划希望将嘌呤能信号传导的基本问题转化为缺氧诱导血管生成的临床相关问题。VVEC血管生成表型的表征，包括嘌呤能受体和偶联信号通路，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。