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）对退伍军人的健康具有毁灭性影响，是导致退伍军人死亡的主要原因 CVD 的早期病理学特征是血管反应性受损（收缩）。 因为脉管系统具有分配营养和调节血液的关键功能。 压力，重要的是要针对血管的早期功能障碍，以进一步了解和预防这种情况 我们最近将大鼠饲养在热中性（TN）条件下，并观察到其衰弱的情况。 女性的血管反应性和高血压，从而产生了非常适合进一步研究的动物模型 考虑到血管周围脂肪组织 (PVAT) 的 CVD 研究和性别差异。 棕色脂肪组织 (BAT) 围绕并调节 PVAT 的脉管系统重塑或变化。 从 BAT 到白色脂肪组织 (WAT) 的 PVAT 表型，可能会导致 PVAT 旁分泌功能障碍 在一项初步研究中，我们将大鼠饲养在室温 (RT) 或 TN 条件下。 研究了它们自己的 PVAT 或来自对面饲养的动物的 PVAT 以及每只大鼠自己的主动脉 在用 RT 饲养动物的 PVAT 分析 TN 饲养动物的主动脉中， 血管表现出血管舒张能力显着增加，强烈表明PVAT不仅 调节血管反应性，但可以修复持续观察到的 TN 引起的扩张减弱。 PVAT 美白会导致脉管系统的旁分泌信号传导机制减弱，从而导致 此外，性别作为生物学变量决定了血管反应性减弱的病理学。 我们将确定血管组织的功能障碍是否由 PVAT 和脉管系统串扰控制。 与 PVAT 美白相关的 PVAT 旁分泌信号改变，定义雌激素对 PVAT 的影响 美白和血管功能障碍，并阐明 PVAT 重塑是否会驱动 β-肾上腺素能的改变 支持这些目标的实验结果不仅会产生新的数据。 TN 诱导的 PVAT 对雌性和雄性大鼠脉管系统和线粒体代谢的调节，而且 查明所有患有 CVD 退伍军人血管功能受损治疗方式的性别差异。