Zhu Terry, Chiacchia Samuel, Kameny Rebecca J, Garcia De Herreros Antoni, Gong Wenhui, Raff Gary W, Boehme Jason B, Maltepe Emin, Lasheras Juan C, Black Stephen M, Datar Sanjeev A, Fineman Jeffrey R
Department of Pediatrics, University of California, San Francisco, CA, USA.
Institute of Engineering in Medicine, University of California, San Diego, CA, USA.
Pulm Circ. 2020 May 14;10(2):2045894020922118. doi: 10.1177/2045894020922118. eCollection 2020 Apr-Jun.
The risk and progression of pulmonary vascular disease in patients with congenital heart disease is dependent on the hemodynamics associated with different lesions. However, the underlying mechanisms are not understood. Endothelin-1 is a potent vasoconstrictor that plays a key role in the pathology of pulmonary vascular disease. We utilized two ovine models of congenital heart disease: (1) fetal aortopulmonary graft placement (shunt), resulting in increased flow and pressure; and (2) fetal ligation of the left pulmonary artery resulting in increased flow and normal pressure to the right lung, to investigate the hypothesis that high pressure and flow, but not flow alone, upregulates endothelin-1 signaling. Lung tissue and pulmonary arterial endothelial cells were harvested from control, shunt, and the right lung of left pulmonary artery lambs at 3-7 weeks of age. We found that lung preproendothelin-1 mRNA and protein expression were increased in shunt lambs compared to controls. Preproendothelin-1 mRNA expression was modestly increased, and protein was unchanged in left pulmonary artery lambs. These changes resulted in increased lung endothelin-1 levels in shunt lambs, while left pulmonary artery levels were similar to controls. Pulmonary arterial endothelial cells exposed to increased shear stress decreased endothelin-1 levels by five-fold, while cyclic stretch increased levels by 1.5-fold. These data suggest that pressure or an additive effect of pressure and flow, rather than increased flow alone, is the principal driver of increased endothelin signaling in congenital heart disease. Defining the molecular drivers of the pathobiology of pulmonary vascular disease due to differing mechanical forces will allow for a more targeted therapeutic approach.
先天性心脏病患者肺血管疾病的风险和进展取决于与不同病变相关的血流动力学。然而，其潜在机制尚不清楚。内皮素-1是一种强效血管收缩剂，在肺血管疾病的病理过程中起关键作用。我们利用了两种先天性心脏病绵羊模型：（1）胎儿主动脉肺动脉分流移植（分流），导致血流量和压力增加；（2）胎儿左肺动脉结扎，导致右肺血流量增加且压力正常，以研究高压和高流量而非单纯高流量上调内皮素-1信号传导的假设。在3至7周龄时，从对照、分流以及左肺动脉结扎的羔羊的右肺中采集肺组织和肺动脉内皮细胞。我们发现，与对照组相比，分流羔羊的肺前内皮素-1 mRNA和蛋白表达增加。左肺动脉结扎的羔羊前内皮素-1 mRNA表达略有增加，而蛋白表达未改变。这些变化导致分流羔羊的肺内皮素-1水平升高，而左肺动脉结扎的羔羊的肺内皮素-1水平与对照组相似。暴露于增加的剪切应力下的肺动脉内皮细胞使内皮素-1水平降低了五倍，而周期性拉伸使内皮素-1水平升高了1.5倍。这些数据表明，压力或压力与流量的叠加效应而非单纯流量增加是先天性心脏病中内皮素信号增加的主要驱动因素。确定由于不同机械力导致的肺血管疾病病理生物学的分子驱动因素将有助于采取更具针对性的治疗方法。
