ROLE OF ADENOSINE IN COORDINATING CARDIOMYOCYTE FUNCTION AND VASCULAR GROWTH IN

腺苷在协调心肌细胞功能和血管生长中的作用

• 批准号: 8521733
• 负责人: LOWELL E DAVIS
• 金额: $ 18.62万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8521733
• 关键词: 5' -Nucleotidase; Acute; Adenosine; Adenosine A3 Receptor; Adenosine Kinase; Adrenergic Receptor; Adult; Agonist; Anatomy; Anemia; Animals; Attenuated; Automobile Driving; Biological Preservation; Blood Pressure; Blood Vessels; Blood capillaries; Blood flow; Body Weight; Brain natriuretic peptide; Bromodeoxyuridine; Cardiac; Cardiac Myocytes; Cardiac Output; Cell Culture Techniques; Cell Hypoxia; Cell Proliferation; Chronic; Clinical; Control Animal; Coronary; Coronary Arteriosclerosis; Development; Discipline of obstetrics; Disease; Endothelial Cells; Environment; Fetus; Growth; Heart; Heart Diseases; Heart failure; Hyperplasia; Hypertrophy; Hypoxemia; Hypoxia; In Vitro; Infarction; Ischemia; Judgment; Knowledge; Laboratories; Lead; Life; Link; MAP Kinase Gene; MEKs; Measures; Mediator of activation protein; Mitogen-Activated Protein Kinases; Modeling; Muscle Cells; Myocardial; Myocardium; Nucleoside Transporter; Oxygen; PIK3CG gene; Pathway interactions; Phosphorylation; Pregnancy; Proto-Oncogene Proteins c-akt; Purinergic P1 Receptors; Receptor Signaling; Reperfusion Therapy; Research; Risk; Role; Sheep; Signal Pathway; Signal Transduction; Source; Stimulus; Stroke Volume; Techniques; Testing; Time; Update; Vascular Endothelial Growth Factors; Vascular remodeling; Vascular resistance; Vascularization; Ventricular Remodeling; adenosine deaminase; capillary; capillary bed; density; design; extracellular; falls; fetal; improved; in utero; in vivo; indexing; insight; interstitial; mature animal; programs; response; sound

Project I will study the role of adenosine in coordinating fetal coronary vascular growth and myocyte function during conditions of hypoxemia in the heart, as well as the long-term consequences of altered adenosine signaling in fetal life upon cardiac function in the adult. Studies using a model of fetal anemia to study fetal hypoxemia have shown that fetal adaptations for survival include a 30% increase in heart to body weight ratio, a 50% increase in stroke volume and cardiac output, a 6-fold increase in coronary blood flow and a doubling of coronary conductance with preservation of coronary reserve. This occurs in the face of a fall in fetal systemic arterial blood pressure and vascular resistance. Changes include an increase in myocardial HIF-1a and VEGF, and an increase in cardiac capillary volume density in both ventricles. Ventricular remodeling occurs with both myocyte hyperplasia and hypertrophy as eccentric hypertrophy normalizes wall tension. The vascular remodeling changes found in the fetus persist in the adult, and lead to greater myocardial damage following ischemia/reperfusion. A critical link between fetal environment and adult disease that is missing is the step that coordinates fetal myocyte and vascular growth and function. Aim 1 will test the hypothesis that intracellular adenosine signaling regulates fetal coronary vascular growth and cardiomyocyte function in fetal hypoxemia. In Aim 2, we will study the in vivo and in vitro role of intracellular MAP kinase (also called extracellular signal-regulated kinase, or ERK) signaling on adenosine-stimulated fetal coronary growth and myocardial function. In Aim 3 we will determine the long-term consequences of either reduced or increased fetal adenosine receptor signaling upon coronary conductance and myocardial function in adulthood with the use of adenosine receptor specific agonists/antagonists.

项目一将研究腺苷在协调胎儿冠状血管生长和肌细胞功能中的作用 在心脏低氧血症的情况下，以及腺苷改变的长期后果 胎儿生命中的信号传导对成人心脏功能的影响。使用胎儿贫血模型来研究胎儿的研究 低氧血症表明，胎儿的生存适应包括心脏与体重之比增加 30%， 每搏输出量和心输出量增加 50%，冠状动脉血流量增加 6 倍，心率增加一倍 冠状动脉电导与冠状动脉储备的保存。这种情况发生在胎儿全身系统下降时 动脉血压和血管阻力。变化包括心肌 HIF-1a 和 VEGF 的增加， 以及两个心室的心脏毛细血管体积密度增加。心室重塑同时发生 肌细胞增生和肥大，因为离心肥大使壁张力正常化。胎儿中发现的血管重塑变化在成人中持续存在，并导致缺血/再灌注后更大的心肌损伤。胎儿环境与成人疾病之间缺少的一个关键联系是 协调胎儿肌细胞和血管的生长和功能。目标 1 将检验细胞内腺苷信号传导在胎儿低氧血症中调节胎儿冠状血管生长和心肌细胞功能的假设。在目标 2 中，我们将研究细胞内 MAP 激酶（也称为细胞外信号调节激酶，或 ERK）信号对腺苷刺激的胎儿冠状动脉生长和心肌功能的体内和体外作用。在目标 3 中，我们将通过使用腺苷受体特异性激动剂/拮抗剂来确定胎儿腺苷受体信号传导减少或增加对成年后冠状动脉电导和心肌功能的长期影响。