Formyl peptide receptor activation induces vascular plasticity and remodeling inhypertension

甲酰基肽受体激活诱导高血压血管可塑性和重塑

• 批准号: 10460675
• 负责人: Camilla Ferreira Wenceslau
• 金额: $ 36万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10460675
• 关键词: Actins; Advanced Development; Affect; Animals; Arteries; Attention; Bacteria; Binding; Blood; Blood Circulation; Blood Pressure; Blood Vessels; Cell Death; Cells; Characteristics; Data; Enzymes; FPR1 gene; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Genetic Engineering; Germ-Free; Goals; Human; Hypertension; Immune; Immune system; Immunobiology; Inflammation; Infusion procedures; Innate Immune System; Institutional Review Boards; Interdisciplinary Study; Intrinsic factor; Lead; Leaky Gut; Legal patent; Leukocytes; Link; Lipopolysaccharides; Literature; Measures; Mediating; Mitochondria; Modeling; Molecular; Movement; National Heart, Lung, and Blood Institute; Patients; Pattern recognition receptor; Peptides; Play; Rattus; Receptor Activation; Research; Research Personnel; Research Project Grants; Role; Sentinel; Signal Pathway; Source; Technology; Testing; Therapeutic; Time; Translational Research; Vascular Diseases; Vascular remodeling; arterial remodeling; base; cell injury; cell motility; driving force; fMet-Leu-Phe receptor; formyl peptide; gut microbiota; innate immune function; innovation; microbiota; network dysfunction; neutrophil; normotensive; novel; novel therapeutic intervention; pathogen; polymerization; pressure; prevent; receptor; sensor; translational study; vascular injury

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. 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, because it is unique, innovative and it 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.

项目概述：