Endothelial to mesenchymal transition during neonatal hyperoxia-induced pulmonary hypertension.
Endothelial to mesenchymal transition during neonatal hyperoxia-induced pulmonary hypertension.
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DOI：
10.1002/path.5534
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Yao H
中科院分区：
文献类型：
--
作者：
Gong J;Feng Z;Peterson AL;Carr JF;Vang A;Braza J;Choudhary G;Dennery PA;Yao H
支气管肺发育不良（BPD）是早产儿的一种慢性肺部疾病，由机械通气和高氧等因素引起。虽然大多数BPD幸存者可以脱离辅助供氧，但许多人在成年后表现出心血管后遗症的证据，包括肺动脉高压和肺血管重塑。内皮-间质转化（EndoMT）在特发性肺动脉高压血管重构中起重要作用。高氧暴露（啮齿动物模型中BPD的已知介质）是否引起导致血管重塑和肺动脉高压的EndoMT仍不清楚。我们假设新生儿高氧暴露导致EndoMT，导致成年后肺动脉高压的发展。为了验证这一假设，新生小鼠暴露于高氧，然后允许在室内空气中恢复，直到成年。新生儿高氧暴露逐渐引起肺血管和右心室重构以及肺动脉高压。当雄性小鼠在新生时暴露于高氧时，与雌性小鼠相比，雄性小鼠更容易发生肺动脉高压。高氧暴露诱导小鼠肺以及从新生小鼠和人胎儿供体分离的培养的肺微血管内皮细胞（LMVECs）中的EndoMT。与来自女性供体的培养LMVEC相比，来自男性供体的培养LMVEC中这一点有所增加。使用原代小鼠LMVECs，高氧暴露增加了Smad 2和Smad 3的磷酸化，但降低了Smad 7蛋白水平。用选择性TGF-β抑制剂SB 431542处理在体外阻断高氧诱导的EndoMT。总之，我们发现新生儿高氧暴露导致血管重塑和肺动脉高压在成年期。这与EndoMT增加有关。这些新的观察结果提供了高氧诱导的血管重塑的潜在机制和通过靶向EndoMT预防BPD相关肺动脉高压的潜在方法。
Bronchopulmonary dysplasia (BPD), a chronic lung disease in premature infants, results from mechanical ventilation and hyperoxia, amongst other factors. Although most BPD survivors can be weaned from supplemental oxygen, many show evidence of cardiovascular sequelae in adulthood, including pulmonary hypertension and pulmonary vascular remodeling. Endothelial–mesenchymal transition (EndoMT) plays an important role in mediating vascular remodeling in idiopathic pulmonary arterial hypertension. Whether hyperoxic exposure, a known mediator of BPD in rodent models, causes EndoMT resulting in vascular remodeling and pulmonary hypertension remains unclear. We hypothesized that neonatal hyperoxic exposure causes EndoMT, leading to the development of pulmonary hypertension in adulthood. To test this hypothesis, newborn mice were exposed to hyperoxia and then allowed to recover in room air until adulthood. Neonatal hyperoxic exposure gradually caused pulmonary vascular and right ventricle remodeling as well as pulmonary hypertension. Male mice were more susceptible to developing pulmonary hypertension compared to female mice, when exposed to hyperoxia as newborns. Hyperoxic exposure induced EndoMT in mouse lungs as well as in cultured lung microvascular endothelial cells (LMVECs) isolated from neonatal mice and human fetal donors. This was augmented in cultured LMVECs from male donors compared to those from female donors. Using primary mouse LMVECs, hyperoxic exposure increased phosphorylation of both Smad2 and Smad3, but reduced Smad7 protein levels. Treatment with a selective TGF-β inhibitor SB431542 blocked hyperoxia-induced EndoMT in vitro. Altogether, we show that neonatal hyperoxic exposure caused vascular remodeling and pulmonary hypertension in adulthood. This was associated with increased EndoMT. These novel observations provide mechanisms underlying hyperoxia-induced vascular remodeling and potential approaches to prevent BPD-associated pulmonary hypertension by targeting EndoMT.
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影响因子：
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作者：
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