Background

Obesity is a major risk factor for diabetes and cardiovascular diseases such as hypertension, heart failure, and stroke. Impaired endothelial function occurs in the earliest stages of obesity and underlies vascular alterations that give rise to cardiovascular disease. However, the mechanisms that link weight gain to endothelial dysfunction are ill-defined. Increasing evidence suggests that endothelial cells are not a population of uniform cells but are highly heterogeneous and are organized as a communicating multicellular network that controls vascular function.

Purpose

To investigate the hypothesis that disrupted endothelial heterogeneity and network-level organization contribute to impaired vascular reactivity in obesity.

Methods and Results

To study obesity-related vascular function without complications associated with diabetes, a state of prediabetic obesity was induced in rats. Small artery diameter recordings confirmed nitric-oxide mediated vasodilator responses were dependent on increases in endothelial calcium levels and were impaired in obese animals. Single-photon imaging revealed a linear relationship between blood vessel relaxation and population-wide calcium responses. Obesity did not alter the slope of this relationship, but impaired calcium responses in the endothelial cell network. The network comprised structural and functional components. The structural architecture, a hexagonal lattice network of connected cells, was unchanged in obesity. The functional network contained sub-populations of clustered specialized agonist-sensing cells from which signals were communicated through the network. In obesity there were fewer but larger clusters of sensory cells and communication path lengths between clusters increased. Communication between neighboring cells was unaltered in obesity. Altered network organization resulted in impaired, population-level calcium signaling and deficient endothelial control of vascular tone.

Conclusions

The distribution of cells in the endothelial network is critical in determining overall vascular response. Altered cell heterogeneity and arrangement in obesity decreases endothelial function and provides a novel framework for understanding compromised endothelial function in cardiovascular disease.

中文翻译：

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内皮细胞异质性和网络组织的破坏会损害糖尿病前期肥胖的血管功能。

 背景

肥胖是糖尿病和高血压、心力衰竭和中风等心血管疾病的主要危险因素。内皮功能受损发生在肥胖的最早阶段，是导致心血管疾病的血管改变的基础。然而，体重增加与内皮功能障碍之间的联系机制尚不明确。越来越多的证据表明，内皮细胞不是一群均匀的细胞，而是高度异质的，并被组织为控制血管功能的通信多细胞网络。

 目的

调查以下假设：内皮异质性和网络水平组织的破坏导致肥胖症中血管反应性受损。

 方法和结果

为了研究肥胖相关的血管功能而不出现与糖尿病相关的并发症，在大鼠中诱导糖尿病前期肥胖状态。小动脉直径记录证实，一氧化氮介导的血管舒张反应依赖于内皮钙水平的增加，并且在肥胖动物中受到损害。单光子成像揭示了血管舒张与人群钙反应之间的线性关系。肥胖不会改变这种关系的斜率，但会损害内皮细胞网络中的钙反应。该网络由结构和功能组件组成。结构体系，即连接细胞的六角形晶格网络，在肥胖中没有变化。该功能网络包含聚集的专门激动剂传感细胞的亚群，这些细胞的信号通过网络进行通信。在肥胖症中，感觉细胞簇较少但较大，并且簇之间的通信路径长度增加。肥胖时相邻细胞之间的通讯没有改变。网络组织的改变导致群体水平的钙信号传导受损以及内皮细胞对血管张力的控制不足。

 结论

内皮网络中细胞的分布对于确定整体血管反应至关重要。肥胖中细胞异质性和排列的改变会降低内皮功能，并为理解心血管疾病中受损的内皮功能提供了一个新的框架。