Extracellular ATP as regulator of hypoxia-induced vasa vasorum neovascularization

细胞外 ATP 作为缺氧诱导的滋养血管新生血管的调节剂

• 批准号: 9041653
• 负责人: Evgenia V Gerasimovskaya
• 金额: $ 48.9万
• 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 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9041653
• 关键词: Adenine Nucleotides; Animals; Bioenergetics; Biological; Blood Cells; Blood Vessels; Cardiac; Cell Culture Techniques; Cell Respiration; Cells; Chronic; Data; Development; Disease; Endothelial Cells; Energy Metabolism; Exhibits; FRAP1 gene; Glycolysis; Goals; Growth; Health; Human; Hypoxia; Infiltration; Inflammatory; Life; Link; Lung; MAPK3 gene; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Neonatal; Nucleotides; Pathogenesis; Pathologic Neovascularization; Pathway interactions; Phenotype; Physiological; Play; Population; Pulmonary Circulation; Pulmonary Hypertension; Pulmonary artery structure; Purinoceptor; Rattus; Regulation; Reporting; Research Proposals; Role; Signal Pathway; Signal Transduction; Source; Stem cells; Stimulus; Testing; Translating; Tunica Adventitia; Vascular Diseases; Vascular Endothelial Cell; Vascular remodeling; Warburg Effect; Work; angiogenesis; autocrine; cell type; clinically relevant; density; effective therapy; extracellular; innovation; neovascularization; paracrine; progenitor; pulmonary arterial hypertension; receptor-mediated signaling; response; vasa vasorum; vasculogenesis

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 previously reported tha We have previously reported that similar to humans with IPAH, hypoxia-induced pulmonary artery (PA) remodeling is associated with marked increases in the density of vasa vasorum (VV) network, recruitment and infiltration of circulating progenitor and inflammatory cells to the PA, implicating VV in disease pathogenesis. The long-term goal of our studies is to evaluate 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. We demonstrated that the adventitial vasa vasorum endothelial cells (VVEC) are a potent source of extracellular ATP, which acts as an autocrine/paracrine factor mediating hypoxia-induced VVEC angiogenesis. Our data demonstrated that exaggerated nucleotide-mediated angiogenic responses in VVEC involve activation of P2Y1, and P2Y13 purinergic receptors, PI3K/Akt/mTOR, ERK1/2, and the elevation of cytoplasmic, nucleoplasmic, and mitochondrial Ca2+. In addition, our preliminary data for this proposal we demonstrated the presence of subsets of P2Y13R expressing highly proliferative potential colony forming cells (VVECFC) in VVEC cultures, which might be responsible for angiogenic VV expansion. As the importance of cellular energy metabolism has been postulated to link cellular metabolic state and functional responses, in this proposal we will test the hypothesis that purinergic regulation of VV angiogenesis involves the activation of mitogenic and bioenergetic pathways in VVEC and VVECFC, leading to metabolic reorgnization/reprogramming and phenotypical changes in these cells towards differentiated endothelial phenotype. The studies proposed in three specific aims will: (i) Characterize a hierarchy of colony-forming cells residing in VVEC; determine their phenotype, proliferative and angiogenic capabilities; (ii) examine purinergic receptor-mediated signaling pathway in clonogenic, angiogenic, and signaling responses in VVEC and VVECFC; (iii) determine bioenergetic organization of VVEC and VVECFC and determine whether extracellular nucleotides and hypoxia induce angiogenic and phenotypic responses in these cells via energy metabolism and mitochondrial regulation. Ultimately, this research proposal aspires to translate fundamental questions of purinergic signaling to the clinically relevant problem of hypoxia-induced angiogenesis. Understanding of fundamental biological mechanisms of metabolic and signaling regulation of VV expansion to a functional vascular network will facilitate development of the innovative treatments for pulmonary hypertension and a variety of vascular diseases that involve impaired angiogenesis and pathologic vascular remodeling.

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。在缺氧性肺动脉高压的新生儿模型中，我们先前已经报道了与人类类似的人类，与伊帕（IPAH）相似，缺氧诱导的肺动脉（PA）重塑与Vasa Gasorum（VV）网络，募集和渗透性细胞的疾病和炎症细胞的密度显着增加有关。我们研究的长期目标是评估细胞机制和内源性分子因子，这些因素介导缺氧诱导的肺血管重塑中的VASA血管内新生血管形成。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。我们证明了外来的VASA血管内皮细胞（VVEC）是细胞外ATP的有效来源，它充当了介导缺氧诱导的VVEC血管生成的自分泌/旁分泌因子。我们的数据表明，VVEC中夸张的核苷酸介导的血管生成反应涉及P2Y1的激活，P2Y13嘌呤能受体，PI3K/AKT/MTOR，ERK1/2，以及细胞质，核肿瘤，核肿瘤和线粒体CA2+的升高。此外，我们对该提案的初步数据证明了在VVEC培养物中表达高度增殖的潜在菌落形成细胞（VVECFC）的P2Y13R的子集的存在，这可能负责血管生成VV的扩张。由于已经假定了细胞能量代谢的重要性在将细胞代谢状态和功能反应联系起来，因此在这项建议中，我们将检验以下假说：VV血管生成的嘌呤能调节涉及有丝分裂和生物能途径的激活VVEC和VVECFC中的细胞代谢重新构建和现实的现有变化。提出的三个特定目的的研究将：（i）表征位于VVEC中的菌落形成细胞的层次结构；确定其表型，增殖和血管生成能力； （ii）检查VVEC和VVECFC中克隆，血管生成和信号反应中的嘌呤能受体介导的信号传导途径； （iii）确定VVEC和VVECFC的生物能组织，并确定细胞外核苷酸和缺氧是否通过能量代谢和线粒体调节诱导这些细胞中的血管生成和表型反应。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。了解对功能性血管网络扩展的代谢和信号调节的基本生物学机制将有助于开发用于肺动脉高压的创新处理，以及涉及涉及刺激性血管生成和病理血管重塑的各种血管疾病。