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: 9249659
• 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 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9249659
• 关键词: Adenine Nucleotides; Alpha Cell; Animals; Bioenergetics; Biological; Blood Cells; Blood Vessels; Cardiac; Cell Culture Techniques; Cell Differentiation process; Cell Respiration; Cells; Chronic; Data; Development; Disease; Endothelial Cells; Energy Metabolism; Exhibits; FRAP1 gene; Glycolysis; Goals; Growth; Human; Hypoxia; Impairment; Infiltration; Inflammatory; Life; Link; Lung; MAPK3 gene; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Neonatal; Nucleotides; Pathogenesis; Pathologic; Pathway interactions; Phenotype; Physiological; Play; Population; Pulmonary Circulation; Pulmonary Hypertension; Pulmonary artery structure; Purinoceptor; Rattus; Recruitment Activity; 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; angiogenesis; autocrine; cell type; clinically relevant; density; effective therapy; extracellular; innovation; metabolic phenotype; neovascularization; paracrine; progenitor; public health relevance; pulmonary arterial hypertension; 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（由申请方提供）：病理性血管重塑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。在缺氧性肺动脉高压的新生儿模型中，我们以前曾报道过，与IPAH患者相似，缺氧诱导的肺动脉（PA）重塑与血管（VV）网络密度的显著增加、循环祖细胞和炎性细胞向PA的募集和浸润相关，提示VV在疾病发病机制中起作用。本研究的长期目标是评估缺氧诱导的肺血管重构中介导血管新生的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。我们证明，外膜血管内皮细胞（VVEC）是一个有效的来源，细胞外ATP，作为一个自分泌/旁分泌因子介导缺氧诱导的VVEC血管生成。我们的数据表明，夸大的核苷酸介导的血管生成反应在VVEC涉及激活P2 Y1和P2 Y13嘌呤受体，PI 3 K/Akt/mTOR，ERK 1/2，和细胞质，核质和线粒体Ca 2+的升高。此外，我们的初步数据表明，在VVEC培养物中存在表达P2 Y13 R的高增殖潜力集落形成细胞（VVECFC）的亚群，这可能是血管生成VV扩增的原因。由于细胞能量代谢的重要性已被假定为连接细胞代谢状态和功能反应，在本提案中，我们将测试的假设，嘌呤调节VV血管生成涉及激活VVEC和VVECFC中的促有丝分裂和生物能量途径，导致代谢重组/重编程和表型变化，这些细胞向分化的内皮细胞表型。本研究拟从三个方面进行研究：（i）研究VVEC中集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）研究嘌呤能受体介导的VVEC和VVECFC中集落形成、血管生成和信号传导反应的信号通路;（三）确定VVEC和VVECFC的生物能量组织，并确定细胞外核苷酸和缺氧是否诱导这些细胞中的血管生成和表型反应。细胞通过能量代谢和线粒体调节。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。了解VV扩展到功能性血管网络的代谢和信号调节的基本生物学机制将促进肺动脉高压和涉及受损血管生成和病理性血管重塑的各种血管疾病的创新治疗的发展。

项目成果

Vascular remodeling 2018: the updates.

2018 年血管重塑：更新。

• DOI: 10.20517/2574-1209.2019.11
• 发表时间: 2019
• 期刊: Vessel plus
• 作者: Gerasimovskaya,Evgenia;Verin,Alexander
• 通讯作者: Verin,Alexander

PI3K, Rho, and ROCK play a key role in hypoxia-induced ATP release and ATP-stimulated angiogenic responses in pulmonary artery vasa vasorum endothelial cells.

PI3K、Rho 和 ROCK 在缺氧诱导的肺动脉血管内皮细胞 ATP 释放和 ATP 刺激的血管生成反应中发挥关键作用。

• DOI: 10.1152/ajplung.00038.2009
• 发表时间: 2009
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: Woodward,HeatherN;Anwar,Adil;Riddle,Suzette;Taraseviciene-Stewart,Laimute;Fragoso,Miguel;Stenmark,KurtR;Gerasimovskaya,EvgeniaV
• 通讯作者: Gerasimovskaya,EvgeniaV

Complementary effects of extracellular nucleotides and platelet-derived extracts on angiogenesis of vasa vasorum endothelial cells in vitro and subcutaneous Matrigel plugs in vivo.

• DOI: 10.1186/2045-824x-3-4
• 发表时间: 2011-02-02
• 期刊: Vascular cell
• 作者: Roedersheimer M;Nijmeh H;Burns N;Sidiakova AA;Stenmark KR;Gerasimovskaya EV
• 通讯作者: Gerasimovskaya EV

Adenosine A1 receptors promote vasa vasorum endothelial cell barrier integrity via Gi and Akt-dependent actin cytoskeleton remodeling.

• DOI: 10.1371/journal.pone.0059733
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Umapathy SN;Kaczmarek E;Fatteh N;Burns N;Lucas R;Stenmark KR;Verin AD;Gerasimovskaya EV
• 通讯作者: Gerasimovskaya EV