Endothelial PHD2 in hypertensive vascular remodeling

内皮PHD2在高血压血管重塑中的作用

• 批准号: 10477185
• 负责人: JIAN-XIONG CHEN
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10477185
• 关键词: ARG2 gene; Angiotensins; Aorta; Attenuated; BMP2 gene; Basement membrane; Blood; Blood Vessels; Blood capillaries; Blood flow; CSPG4 gene; Cardiovascular system; Cells; Clinic; Clinical; Coronary; Data; Differentiated Gene; Differentiation Antigens; Disease; Endothelium; Equilibrium; Etiology; Fibroblasts; Fibrosis; Functional disorder; HMG-Box Domains; Heart; Hypertension; Incidence; Kidney; Knock-out; Lung; Maintenance; Mediating; Mesenchymal; Mesenchymal Stem Cells; Metabolic; Molecular; Mus; Myofibroblast; NOTCH3 gene; Osteoblasts; Outcome; Oxygen; Pericytes; Pharmacology; Procollagen-Proline Dioxygenase; Production; Regulation; Reporter; Reporting; Role; Signal Pathway; Smooth Muscle Myocytes; Source; Tertiary Protein Structure; Testing; Thick; Triad Acrylic Resin; Up-Regulation; Vascular Smooth Muscle; Vascular calcification; Vascular remodeling; angiogenesis; arginase; arterial remodeling; arterial stiffness; base; calcification; drug discovery; hypertensive; inhibitor; mortality; novel; osteogenic; osteopontin; recruit; sensor; therapeutic target

Summary: Arterial stiffness is the center feature of hypertension and has significant impact upon disease etiology and outcomes. So far, there is no cure for hypertensive arterial stiffness. Therefore, it is urgent to identify potential therapeutic targets that can reduce hypertensive arterial stiffness. Emerging evidence indicates that pericyte is a novel target of angiogenesis and vascular remodeling. Pericytes are a subpopulation of mesenchymal stem cells which can differentiate into osteoblasts, vascular smooth muscle cells (VSMCs) and fibroblasts. Pericytes promotes fibrosis formation via pericyte-(myo)-fibroblast transition (PFT). Pericyte also has been shown to differentiate into VSMCs at arterial remodeling zones in the heart. Our recent study found that deletion of oxygen sensor prolyl hydroxylase-2 (PHD2) in the endothelium resulted in excessive pericyte recruitment and arterial stiffness, and exacerbation of angiotensin II (Ang-II)-induced hypertension. Knockout of endothelial PHD2 caused an imbalanced arginase-2/eNOS favoring in arginase-2. Furthermore, knockout of endothelial PHD2 significantly increased osteogenic differentiation markers (SOX9, BMP2 and osteopontin) in the aorta and promoted VSMC calcification. Using NG2 pericyte tracing reporter NG2DsRedBAC mice, our preliminary study further suggested an important role of NG2+ pericyte in Ang-II mediating vascular remodeling. Based on our findings, we hypothesize that deactivation of PHD2 in EC enhances arterial stiffness and hypertension by the mechanisms involving an imbalanced arginase-2/eNOS and pericyte differentiation into VSMCs, osteogenic cells and fibroblasts via HIF-2α-PFKFB3 signaling pathway. Two specific aims will be proposed to test: Aim 1: To define the molecular mechanisms by which endothelial PHD2 regulates arterial stiffness with a focus on an imbalanced arginase-2/eNOS. We will determine: (i) whether deficiency of endothelial PHD2 induces an imbalanced arginase-2/eNOS via HIF-2α-PFKFB3 signaling pathway, (ii) whether pharmacologic blockade of HIF-2α using a clinic relevant and highly specific inhibitor PT2385 attenuates PFKFB3 expression, restores arginase-2/eNOS balances and reduces Ang-II-induced arterial stiffness in PHD2ECKO mice; and (3) whether knockout of arginase-2 reduces vascular remodeling and arterial stiffness in PHD2ECKO mice. Aim 2: To define the role of PHD2- PFKFB3 in mediating pericyte differentiation and hypertensive arterial stiffness. Using pericyte tracing reporter NG2DsRedBAC (Tg) mice crossing with PHD2ECKO mice, we will test whether inhibition of PFKFB3 attenuates osteogenic differentiation of pericytes, and reduces vascular calcification. We will further determine whether pharmacological activation of PHD2 or inhibition of PFKFB3 attenuates Ang- II-induced pericyte-fibroblast/VSMC transition, arterial stiffness and hypertensive vascular remodeling. Our study has clinical translational significance for the understanding of pericytes in vascular stiffness.

动脉僵硬度是高血压病的中心特征，对疾病的发生有重要影响 病因和结果。到目前为止，还没有治愈高血压动脉僵硬的方法。因此迫切 以确定可以降低高血压动脉僵硬度的潜在治疗靶点。新出现的证据 表明周细胞是血管生成和血管重塑的新靶点。周细胞是 间充质干细胞亚群，可分化为成骨细胞、血管平滑肌 肌细胞（VSMC）和成纤维细胞。周细胞通过周细胞-（肌）-成纤维细胞促进纤维化形成 过渡（PFT）。周细胞也被证明在动脉重塑区分化为VSMC 在心脏。我们最近的研究发现，氧传感器脯氨酰羟化酶-2（PHD 2）的缺失， 内皮细胞导致周细胞过度募集和动脉僵硬， 血管紧张素II（Ang-II）诱导的高血压。敲除内皮细胞PHD 2引起了细胞内的不平衡， β-淀粉酶-2/eNOS在β-淀粉酶-2中占优势。此外，敲除内皮PHD 2显著地 增加主动脉中的成骨分化标志物（SOX 9、BMP 2和骨桥蛋白），并促进 VSMC钙化。利用NG 2周细胞示踪报告基因NG 2DsRedBAC小鼠， 进一步表明NG 2+周细胞在Ang-II介导的血管重塑中起重要作用。基于 我们的研究结果，我们假设PHD 2在EC中的失活增强了动脉僵硬度， 高血压的发病机制与血管紧张素转换酶-2/内皮型一氧化氮合酶失衡和周细胞分化有关 通过HIF-2α-PFKFB 3信号通路进入VSMC、成骨细胞和成纤维细胞。两个具体目标 目的1：确定内皮PHD 2的分子机制， 调节动脉硬度，重点是不平衡的血管紧张素转换酶-2/eNOS。我们将确定：（一） 内皮细胞PHD 2缺陷是否通过HIF-2α-PFKFB 3诱导了β-半乳糖苷酶-2/eNOS失衡 信号通路，（ii）是否使用临床相关和高度相关的药物阻断HIF-2α， 特异性抑制剂PT 2385减弱PFKFB 3表达，恢复pFKFB-2/eNOS平衡， 降低PHD 2 ECKO小鼠中Ang-II诱导的动脉僵硬度;以及（3）是否敲除血管生成酶-2 降低PHD 2 ECKO小鼠的血管重塑和动脉僵硬度。目标2：定义PHD 2的角色- PFKFB 3介导周细胞分化和高血压动脉僵硬。使用周细胞示踪 将报告基因NG 2DsRedBAC（Tg）小鼠与PHD 2 ECKO小鼠杂交，我们将测试是否抑制PHD 2 ECKO小鼠的表达。 PFKFB 3减弱周细胞的成骨分化，并减少血管钙化。我们将 进一步确定PHD 2的药理学激活或PFKFB 3的抑制是否减弱Ang-1的表达。 II诱导的周细胞-成纤维细胞/VSMC转变、动脉僵硬度和高血压血管重塑。 我们的研究对于理解周细胞在血管僵硬中的作用具有临床意义。