HIF-1α promotes cellular growth in lymphatic endothelial cells exposed to chronically elevated pulmonary lymph flow.
HIF-1α promotes cellular growth in lymphatic endothelial cells exposed to chronically elevated pulmonary lymph flow.
复制标题
HIF-1α促进淋巴内皮细胞暴露于长期升高的肺淋巴流量。
DOI：
10.1038/s41598-020-80882-1
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发表时间：
2021-01-14
影响因子：
4.6
通讯作者：
Datar SA
中科院分区：
文献类型：
--
作者：
Boehme JT;Morris CJ;Chiacchia SR;Gong W;Wu KY;Kameny RJ;Raff GW;Fineman JR;Maltepe E;Datar SA
淋巴结构的正常生长和发育依赖于积聚间质液体所产生的机械力。然而，长期暴露于慢性淋巴流量增加所产生的病理性机械刺激会导致淋巴功能障碍。传递这些机械力的机制还没有完全被理解。我们的目标是利用体外方法，在解剖和生理背景下，利用大鼠先天性心脏病合并肺血流量增加的动物模型，研究在体内长期暴露于病理性增加的淋巴流量下，改变分离的淋巴管内皮细胞(LECs)生长和代谢的分子机制。为此，妊娠晚期的胎羊在子宫内放置了主肺移植物(分流术)。出生后4周，分离培养对照和分流羔羊的晶状体上皮细胞。定量检测氧化还原状态和细胞增殖情况，并进行转录图谱和代谢组学分析。分流的晶状体上皮细胞在缺氧诱导因子-1α(HIF-1α)水平升高的驱动下表现出过度增殖，并在机械刺激和切应力的作用下上调已知的HIF-1α靶基因的表达。与对照LECs相比，分流LECs表现出糖酵解、TCA循环和有氧呼吸等代谢异常。综上所述，在体内暴露于慢性肺淋巴流量增加的羔羊的LECs是过度增殖的，HIF-1α及其靶基因的表达增强，并在体外表现出中枢碳代谢的改变。重要的是，这些发现为淋巴异常患者提供了具有挑衅性的治疗靶点。
Normal growth and development of lymphatic structures depends on mechanical forces created by accumulating interstitial fluid. However, prolonged exposure to pathologic mechanical stimuli generated by chronically elevated lymph flow results in lymphatic dysfunction. The mechanisms that transduce these mechanical forces are not fully understood. Our objective was to investigate molecular mechanisms that alter the growth and metabolism of isolated lymphatic endothelial cells (LECs) exposed to prolonged pathologically elevated lymph flow in vivo within the anatomic and physiologic context of a large animal model of congenital heart disease with increased pulmonary blood flow using in vitro approaches. To this end, late gestation fetal lambs underwent in utero placement of an aortopulmonary graft (shunt). Four weeks after birth, LECs were isolated and cultured from control and shunt lambs. Redox status and proliferation were quantified, and transcriptional profiling and metabolomic analyses were performed. Shunt LECs exhibited hyperproliferative growth driven by increased levels of Hypoxia Inducible Factor 1α (HIF-1α), along with upregulated expression of known HIF-1α target genes in response to mechanical stimuli and shear stress. Compared to control LECs, shunt LECs exhibited abnormal metabolism including abnormalities of glycolysis, the TCA cycle and aerobic respiration. In conclusion, LECs from lambs exposed in vivo to chronically increased pulmonary lymph flow are hyperproliferative, have enhanced expression of HIF-1α and its target genes, and demonstrate altered central carbon metabolism in vitro. Importantly, these findings suggest provocative therapeutic targets for patients with lymphatic abnormalities.
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影响因子：
5.2
作者：
Han T;Yan J;Chen H;Ji Y;Chen J;Cui J;Shen W;Zou J
通讯作者：
Zou J
影响因子：
20.1
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Hong YK
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Shannon JM
影响因子：
15.9
作者：
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通讯作者：
Hong, Young-Kwon
影响因子：
6
作者：
Fijalkowska, Iwona;Xu, Weiling;Tuder, Rubin M.
通讯作者：
Tuder, Rubin M.