Metabolic control in vascular remodeling
血管重塑中的代谢控制
基本信息
- 批准号:10543542
- 负责人:
- 金额:$ 59.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-03-01 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdultAffectAnimalsAortaAreaArterial InjuryArteriesArteriosclerosisAspartateAtherosclerosisBiological AssayBlood VesselsCadherinsCardiovascular DiseasesCause of DeathCell ProliferationCell WallCell divisionCell physiologyCellsCellular Metabolic ProcessCellular biologyComplexDNA DamageDataDevelopmentDiseaseDorsalElementsEmbryoEmbryonic DevelopmentEndothelial CellsExtracellular MatrixFAT geneFrequenciesFunctional disorderGeneticGoalsGrowthHealthHomeostasisImpairmentInjuryInterventionInvadedKnowledgeLabelLongevityMediatingMetabolic ControlMetabolismMitochondriaMitochondrial DNAModelingMusNADH dehydrogenase (ubiquinone)NeuronsObstructionOxidative PhosphorylationOxygen ConsumptionPathogenesisPathogenicityPathologyPhenotypePlayPopulationPredispositionPreventiveProcessProliferatingProteinsReactive Oxygen SpeciesRegulationResearchRespirationRoleSmooth Muscle MyocytesStructureTestingTherapeuticTimeTissue EngineeringTransplantationTubeVascular DiseasesVascular Smooth MuscleVascular remodelingVascularizationangiogenesiscell behaviorcell growthclinically significantcytokinedisabilityin vivomechanical forcemetabolic phenotypemigrationmouse developmentmouse modelnoveloxidationpharmacologicpostnatalpreventrepairedrespiratoryresponserestenosisrestraintscreeningtherapeutic angiogenesistumorvascular injuryvasculogenesis
项目摘要
Summary
Vascular remodeling is essential for artery formation during embryogenesis and in the
pathogenesis of vascular diseases such as atherosclerosis, restenosis, and transplant-
associated arteriosclerosis in adulthood. Despite this high clinical significance, our incomplete
understanding of the process of vascular remodeling limits current abilities to develop
preventive and therapeutic strategies. Vascular smooth muscle cells (SMCs) are main drivers of
developmental and adult vascular remodeling, but mechanisms underlying SMC activities are
not fully elucidated — in particular, the role of mitochondria and metabolism in this context is
relatively unexplored. The goal of this proposal is to understand mitochondrion-based
mechanisms that regulate SMC phenotype in vascular remodeling. We have shown that the
FAT1 cadherin interacts with and inhibits mitochondrial respiratory complex I, limits SMC
proliferation by restraining mitochondrial respiration, and opposes vascular occlusion after
arterial injury. These findings suggest that respiratory complex I regulates SMC behavior. Our
new preliminary data further support this idea. Loss of complex I subunit NDUFS4 in cultured
SMCs decreases complex I levels and activity, limits the formation of supercomplexes
containing complex I, lowers aspartate levels, and impairs cell growth. In vivo, NDUFS4 is highly
expressed during mouse development in SMCs building the arterial wall, and in adult mice in
SMC-derived cells that form the expanding neointima that accumulates in response to arterial
injury. Preliminary studies with selective NDUFS4 deletion in SMCs suggest that these cells
require respiratory complex I for normal embryogenesis. We hypothesize that complex I
promotes SMC activities important for vascular remodeling during embryogenesis and in
adulthood. We will test this hypothesis in three specific aims that respectively address the
effects of impaired respiratory complex I function 1) on key SMC activities, 2) on mouse
vascular development, and 3) in models of adult vascular homeostasis, injury, and
atherosclerotic disease. These studies will add a new respiratory complex-based angle —
susceptible to pharmacological intervention — to our understanding of how arteries form and
how they respond to injury, with relevance for tissue engineering, therapeutic angiogenesis,
tumor vascularization, and vascular disease.
摘要
血管重塑在胚胎发育和胚胎发育过程中对动脉的形成至关重要。
血管疾病的发病机制,如动脉粥样硬化、再狭窄和移植-
成年期的相关动脉硬化。尽管具有很高的临床意义,但我们的不完整
对血管重塑过程的了解限制了当前能力的发展
预防和治疗策略。血管平滑肌细胞(SMC)是主要的驱动力
发育和成人血管重塑,但SMC活动的机制是
没有完全阐明--特别是线粒体和新陈代谢在这方面的作用
相对未被开发。这项提议的目标是理解基于线粒体的
血管重塑中SMC表型的调节机制。我们已经证明了
FAT1钙粘附素与线粒体呼吸复合体I相互作用并抑制SMC
通过抑制线粒体呼吸而增殖,并反对血管闭塞后
动脉损伤。这些发现表明,呼吸复合体I调节SMC的行为。我们的
新的初步数据进一步支持了这一观点。培养细胞中复合体I亚单位NDUFS4的丢失
SMC降低复合体I水平和活性,限制超复合体的形成
含有复合体I,降低天冬氨酸水平,并损害细胞生长。在体内,NDUFS4高度
在小鼠发育期间,在建造动脉壁的SMC中表达,在成年小鼠中表达
SMC来源的细胞,形成扩张的新生内膜,并因动脉粥样硬化而聚集
受伤。在SMC中选择性缺失NDUFS4的初步研究表明,这些细胞
需要呼吸复合体I才能正常胚胎发育。我们假设这个复合体是
促进SMC在胚胎发育过程中对血管重塑至关重要的活动
成人期。我们将在三个具体目标中测试这个假设,这三个目标分别针对
呼吸复合体功能受损对小鼠SMC关键活动的影响
血管发育,以及3)成人血管动态平衡、损伤和
动脉粥样硬化症。这些研究将增加一个新的基于呼吸复合体的角度--
易受药物干预--取决于我们对动脉形成和发展的理解
它们如何应对损伤,与组织工程、治疗性血管生成、
肿瘤血管形成和血管疾病。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Neutrophil extracellular traps in cardiac hypertrophy: a KLF2 perspective.
- DOI:10.1172/jci156453
- 发表时间:2022-02-01
- 期刊:
- 影响因子:0
- 作者:Riascos-Bernal DF;Sibinga NE
- 通讯作者:Sibinga NE
The FAT1 Cadherin Drives Vascular Smooth Muscle Cell Migration.
- DOI:10.3390/cells12121621
- 发表时间:2023-06-14
- 期刊:
- 影响因子:6
- 作者:Riascos-Bernal, Dario F.;Ressa, Gaia;Korrapati, Anish;Sibinga, Nicholas E. S.
- 通讯作者:Sibinga, Nicholas E. S.
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Nicholas E Sibinga其他文献
Nicholas E Sibinga的其他文献
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{{ truncateString('Nicholas E Sibinga', 18)}}的其他基金
Allograft inflammatory factor-1 and immune tolerance
同种异体移植物炎症因子-1和免疫耐受
- 批准号:
10511362 - 财政年份:2022
- 资助金额:
$ 59.36万 - 项目类别:
Allograft inflammatory factor-1 and immune tolerance
同种异体移植物炎症因子-1和免疫耐受
- 批准号:
10642960 - 财政年份:2022
- 资助金额:
$ 59.36万 - 项目类别:
Beta-catenin in vascular homeostasis and remodeling
β-连环蛋白在血管稳态和重塑中的作用
- 批准号:
9507901 - 财政年份:2017
- 资助金额:
$ 59.36万 - 项目类别:
Beta-catenin in vascular homeostasis and remodeling
β-连环蛋白在血管稳态和重塑中的作用
- 批准号:
9884555 - 财政年份:2017
- 资助金额:
$ 59.36万 - 项目类别:
Colony stimulating factor-1 in graft vascular disease
移植血管疾病中的集落刺激因子-1
- 批准号:
9276113 - 财政年份:2015
- 资助金额:
$ 59.36万 - 项目类别:
Allograft inflammatory factor-1 in atherosclerosis
同种异体移植物炎症因子-1在动脉粥样硬化中的作用
- 批准号:
8913555 - 财政年份:2015
- 资助金额:
$ 59.36万 - 项目类别:
Colony stimulating factor-1 in graft vascular disease
移植血管疾病中的集落刺激因子-1
- 批准号:
8985741 - 财政年份:2015
- 资助金额:
$ 59.36万 - 项目类别:
The Fat1 Cadherin in Atherosclerotic Vascular Disease
Fat1 钙粘蛋白在动脉粥样硬化性血管疾病中的作用
- 批准号:
8109076 - 财政年份:2011
- 资助金额:
$ 59.36万 - 项目类别:
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