Delineating Mechanisms of Impaired Vasoreactivity in Thermoneutrality

描述热中性血管反应性受损的机制

• 批准号: 10701111
• 负责人: Amy Celeste Keller
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701111
• 关键词: Adipose tissue; Adrenergic Agents; Animal Housing; Animal Model; Animals; Aorta; Back; Biological; Blood Vessels; Brown Fat; Cardiovascular Diseases; Cardiovascular Pathology; Cell physiology; Cessation of life; Chronic; Data; Diabetes Mellitus; Disease Progression; Endothelium; Estrogens; Exposure to; Fatty Acids; Fatty acid glycerol esters; Female; Functional disorder; Genetic; Health; Hospitalization; Housing; Human; Hypertension; Impairment; In Vitro; Investigation; Lipids; Measures; Metabolism; Mitochondria; Modality; Nitric Oxide; Norepinephrine; Nutrient; Obesity; Paracrine Communication; Pathogenicity; Pathology; Performance; Phenotype; Physiology; Population; Production; Rattus; Regulation; Respiration; Role; Sex Differences; Signal Pathway; Signal Transduction; Temperature; Testing; Tissue Transplantation; Tissues; United States; Vascular Diseases; Vascular Endothelium; Vasodilation; Vasodilator Agents; Veterans; Woman; adipokines; adiponectin; beta-adrenergic receptor; blood pressure regulation; cardiovascular disorder prevention; cardiovascular disorder risk; cold temperature; constriction; endothelial dysfunction; insight; male; men; metabolomics; mitochondrial metabolism; novel; oxidation; prevent; receptor; repaired; response; sex; translational potential

Cardiovascular disease (CVD) has a devastating impact on Veteran health and is a leading cause of both hospitalization and death. Early pathology of CVD is characterized by impaired vasoreactivity (constriction and dilation). As the vasculature serves the critical functions of distributing nutrients and regulating blood pressure, it is important to target early dysfunction in the vascular to further understand and prevent this chronic pathology. We recently housed rats at thermoneutral (TN) conditions and observed debilitated vasoreactivity along with high blood pressure in females, resulting in an animal model well-suited to further CVD investigation along with sex differences in pathology. Perivascular adipose tissue (PVAT), considered brown adipose tissue (BAT), surrounds and regulates the vasculature. Remodeling of PVAT, or the change in PVAT phenotype from BAT to white adipose tissue (WAT), may cause dysfunction in PVAT’s paracrine signaling to the vessel. In a preliminary study, we housed rats at either room temperature (RT) or TN and investigated their own PVAT or PVAT from the oppositely- housed animals along with each rat’s own aorta for vasoreactivity ex situ. In aorta of TN-housed animals analyzed with PVAT from RT-housed animals, the vessels showed a significant increase in vasodilation capacity, strongly suggesting that PVAT not only regulates vasoreactivity, but can repair consistently observed TN-induced diminished dilation. We hypothesize that PVAT whitening results in diminished paracrine signaling mechanisms to the vasculature, causing damaged vasoreactivity. Furthermore, sex as a biological variable determines the pathology of diminished PVAT and vasculature crosstalk. We will determine whether dysfunction in vascular tissue is governed by altered PVAT paracrine signaling associated with PVAT whitening, define the impact of estrogen on PVAT whitening and vascular dysfunction, and elucidate whether PVAT remodeling drives altered β-adrenergic- induced response to temperature. Experimental results supporting these aims will not only generate novel data on TN-induced PVAT regulation of vasculature and mitochondrial metabolism in female and male rats, but also pinpoint sex differences in treatment modalities for impaired vascular function in all Veterans with CVD.

心血管疾病（CVD）对退伍军人的健康有毁灭性的影响，是 住院和死亡。 CVD的早期病理的特征是血管反应性受损（收缩 和扩张）。由于脉管系统具有分配营养和控制血液的关键功能 压力，靶向血管中早期功能障碍以进一步理解和防止这一点很重要 慢性病理学。我们最近在热核（TN）条件下容纳大鼠，并观察到虚弱的大鼠 血管反应性以及女性的高血压，导致了一种非常适合的动物模型 CVD调查以及病理学的性别差异。考虑到周围脂肪组织（PVAT），被认为 棕色脂肪组织（BAT），环境和调节脉管系统。 PVAT的重塑或更改 从蝙蝠到白色脂肪组织（WAT）的PVAT表型可能会在PVAT的旁分泌中引起功能障碍 向容器发出信号。在一项初步研究中，我们在室温（RT）或TN中饲养大鼠 从相反的动物中调查了自己的PVAT或PVAT，以及每只老鼠自己的主动脉 血管反应性异常。在用RT围式动物进行PVAT分析的TN HOSOD动物的主动脉中， 血管显示血管舒张能力显着增加，强烈表明不仅PVAT 调节血管反应性，但可以始终如一地修复TN诱导的词典减少。我们假设 PVAT美白导致脉管系统的旁分泌信号传导机制减少，导致 血管反应性受损。此外，作为生物变量的性别决定了降低的病理 PVAT和脉管系统串扰。我们将确定血管组织中功能障碍是否受 改变了与PVAT美白有关的PVAT旁分泌信号传导，定义了雌激素对PVAT的影响 美白和血管功能障碍，并阐明PVAT重塑是否改变了β-肾上腺素 - 诱发温度的响应。支持这些目标的实验结果不仅会产生新的数据 关于TN诱导的PVAT调节雌性和雄性大鼠的脉管系统和线粒体代谢的调节，但也 所有CVD退伍军人的血管功能受损的治疗方式的性别差异。