The development of peripheral microvasculopathy with chronic metabolic disease in obese Zucker rats: a retrograde emergence?
The development of peripheral microvasculopathy with chronic metabolic disease in obese Zucker rats: a retrograde emergence?
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肥胖 Zucker 大鼠周围微血管病变伴慢性代谢性疾病的发展：逆行出现？
DOI：
10.1152/ajpheart.00264.2022
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Chan
中科院分区：
文献类型：
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作者：
Halvorson,BraydenD;Menon,NithinJ;Goldman,Daniel;Frisbee,StephanieJ;Goodwill,AdamG;Butcher,JoshuaT;Stapleton,PhoebeA;Brooks,StevenD;d'Audiffret,AlexandreC;Wiseman,RobertW;Lombard,JulianH;Brock,RobertW;Olfert,IMark;Chan
慢性代谢性疾病周围血管病变的研究面临着来自空间（正在研究的分辨率水平或特定组织）和时间起源（发展中的损伤随时间的演变）的不同贡献的挑战。经过多年对骨骼肌血管病变的发展及其功能影响的研究，我们可能会提出一个综合的概念模型，以解决肥胖 Zucker 大鼠 (OZR) 模型中的这些挑战。在代谢疾病的早期阶段，存在心血管疾病风险升高的全身标志物，血管功能障碍的唯一证据是在毛细血管后和集合小静脉，其中白细胞粘附/滚动升高，小静脉内皮功能受损。随着代谢疾病严重程度和持续时间的增加，微血管密度降低变得明显，微血管血细胞比容的变异性增加。随后，出现远端小动脉网络的血流动力学损伤，表现为灌注不均匀性增加和小动脉反应性受损。这种逆行的“功能障碍波”持续存在，造成远端小动脉、毛细血管和静脉微循环的缺陷稳定下来，并损害近端小动脉的反应性、壁力学和灌注分布。这种近端小动脉功能障碍与自灌注骨骼肌内的疲劳抵抗力、充血反应和吸氧能力的增加相平行。总而言之，这些结果提出了慢性代谢疾病周围血管病变逆行发展的概念模型，并为改善健康结果的介入策略的时机和目标提供了见解。新的和值得注意的基于跨越多个尺度和时间的已建立数据库，我们研究了慢性代谢疾病中周围微血管功能障碍的进展。这些数据表明毛细血管后小静脉内皮是血管病变的起始部位。功能障碍、跨越网络结构、血流动力学、血管反应性和灌注的指标以隐秘的逆行方式进展，在很久以后表现为肌肉血流和性能的功能障碍。无症状血管病变进展可能有助于深入了解临床治疗挑战。
The study of peripheral vasculopathy with chronic metabolic disease is challenged by divergent contributions from spatial (the level of resolution or specific tissue being studied) and temporal origins (evolution of the developing impairments in time). Over many years of studying the development of skeletal muscle vasculopathy and its functional implications, we may be at the point of presenting an integrated conceptual model that addresses these challenges within the obese Zucker rat (OZR) model. At the early stages of metabolic disease, where systemic markers of elevated cardiovascular disease risk are present, the only evidence of vascular dysfunction is at postcapillary and collecting venules, where leukocyte adhesion/rolling is elevated with impaired venular endothelial function. As metabolic disease severity and duration increases, reduced microvessel density becomes evident as well as increased variability in microvascular hematocrit. Subsequently, hemodynamic impairments to distal arteriolar networks emerge, manifesting as increasing perfusion heterogeneity and impaired arteriolar reactivity. This retrograde “wave of dysfunction” continues, creating a condition wherein deficiencies to the distal arteriolar, capillary, and venular microcirculation stabilize and impairments to proximal arteriolar reactivity, wall mechanics, and perfusion distribution evolve. This proximal arteriolar dysfunction parallels increasing failure in fatigue resistance, hyperemic responses, and O2uptake within self-perfused skeletal muscle. Taken together, these results present a conceptual model for the retrograde development of peripheral vasculopathy with chronic metabolic disease and provide insight into the timing and targeting of interventional strategies to improve health outcomes.NEW & NOTEWORTHYWorking from an established database spanning multiple scales and times, we studied progression of peripheral microvascular dysfunction in chronic metabolic disease. The data implicate the postcapillary venular endothelium as the initiating site for vasculopathy. Indicators of dysfunction, spanning network structures, hemodynamics, vascular reactivity, and perfusion progress in an insidious retrograde manner to present as functional impairments to muscle blood flow and performance much later. The silent vasculopathy progression may provide insight into clinical treatment challenges.