Formyl peptide receptor activation induces vascular plasticity and remodeling in hypertension

WENCESLAU，CAMILLA F. 高血压的主要病理生理学特征之一是存在血管性高血压。 重塑因此，已经表明100%的高血压受试者呈现小动脉重构。 然而，在理解导致血管重塑的确切触发因素方面，文献中存在空白， 这可能会限制我们充分治疗和预防高血压的能力。 最近的证据表明免疫机制参与了高血压的病理生理学。甲酰肽 FPR-1是一种模式识别受体，在先天免疫功能中起着重要作用 系统事实上，诱导肌动蛋白聚合和中性粒细胞凋亡的最强大的信号通路之一是， 运动由FPR-1介导。最近，我们观察到这种受体在动脉中表达。因此，我们认为， 我们质疑为什么白细胞中对免疫防御和细胞运动至关重要的受体， 在动脉中表达和发挥功能我们观察到，动脉中FPR-1的激活对于动脉粥样硬化的发生是重要的。 肌动蛋白的时间重组，其快速诱导肌动蛋白聚合。 FPR-1是一种G蛋白偶联受体，可与细菌产生的N-甲酰肽结合， 降解有趣的是，线粒体带有它们细菌祖先的特征。因此，双方 线粒体和细菌衍生的肽在其N-末端具有甲酰基。因此，N-甲酰基 肽（NFP），无论来源如何，都被FPR-1识别为病原体，因此在启动 炎症。在这里，我们首次观察到NFP存在于高血压患者的循环中， 动物和人类。因此，这是合理的建议，协同作用的泄漏肠源性细菌， NFP和细胞损伤衍生的线粒体NFP导致FPR-1活化。因此，FPR-1激活 可能是通过肌动蛋白聚合引发血管重塑的触发器，随后是高血压。 这项计划中的研究是唯一适合NHLBI早期研究者（ESI）-研究项目 格兰特（R 01）。它是创新的，并拥有强大的，翻译和多学科的研究团队的合作者 拥有使该项目成功的能力和专业知识。作为一个独立的ESI，我的短期 目标是使用最先进的方法，包括培养压力肌描记术，基因工程技术， 以及人类和动物的动脉来探索血管免疫网络背后的主要驱动力 高血压的功能障碍

PROJECT SUMMARY WENCESLAU, CAMILLA F. One of the major pathophysiological characteristics of hypertension is the presence of vascular remodeling. Accordingly, it has been shown that 100% hypertensive subjects present small artery remodeling. However, there is a gap in the literature in understanding the exact trigger that leads to vascular remodeling, and this may limit our ability to adequately treat and prevent hypertension. Recent evidence implicates immune mechanisms in the pathophysiology of hypertension. Formyl peptide receptor (FPR)-1 is a pattern recognition receptor which plays a crucial role in the function of the innate immune system. In fact, one of the most powerful signaling pathways that induces actin polymerization and neutrophil movement is mediated by FPR-1. Recently, we observed that this receptor is expressed in arteries. Therefore, we questioned why a receptor that is crucial for immune defense and cell motility in leukocytes, would be expressed and functional in arteries? We observed that activation of FPR-1 in arteries is important for the temporal reorganization of actin, which rapidly induces actin polymerization. FPR-1 is a G-protein-coupled receptor that can bind N-formyl peptides produced by bacterial degradation. Interestingly, mitochondria carry hallmarks of their bacterial ancestry. Consequently, both mitochondrial and bacterial-derived peptides have a formyl group at their N-terminus. Therefore, N-formyl peptides (NFPs), regardless of origin, are recognized by FPR-1 as pathogens and thus play a role in the initiation of inflammation. Here, we observed for the first time that NFPs are present in the circulation of hypertensive animals and humans. Therefore, it is plausible to suggest that synergistic action of leaky gut-derived bacteria NFPs and cell damage-derived mitochondria NFPs lead to FPR-1 activation. Consequently, FPR-1 activation maybe the trigger to induce vascular remodeling, via actin polymerization, and subsequently, hypertension. This planned research is uniquely suited to the NHLBI Early Stage Investigator (ESI)-Research Project Grant (R01). It is innovative and has a strong, translational and multi-disciplinary research team of collaborators that have the capabilities and expertise to make this project successful. As an independent ESI, my short-term goal is to use state-of-art approaches, including culture-pressure myographs, genetic-engineering technologies, and arteries from humans and animals to explore a major driving force behind vascular-immune network dysfunction in hypertension.