Department of Molecular Biology, Cell Biology & Biochemistry, Division of Biology and Medicine, Brown University, Providence, RI, USA.
Department of Respiratory and Critical Care Medicine, Second Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, PR China.
J Pathol. 2020 Dec;252(4):411-422. doi: 10.1002/path.5534. Epub 2020 Oct 6.
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. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
支气管肺发育不良（BPD）是一种早产儿慢性肺部疾病，由机械通气和高氧等因素引起。虽然大多数 BPD 幸存者可以从补充氧气中逐渐脱机，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-间充质转化（EndoMT）在介导特发性肺动脉高压的血管重塑中起着重要作用。高氧暴露是否会导致 EndoMT，从而导致成年后发生肺动脉高压，这在啮齿动物模型中仍是未知的。我们假设新生鼠高氧暴露导致 EndoMT，从而导致成年后发生肺动脉高压。为了验证这一假设，我们对新生鼠进行了高氧暴露，然后让其在室内空气中恢复至成年。新生鼠高氧暴露逐渐导致肺血管和右心室重塑以及肺动脉高压。与女性相比，新生时暴露于高氧的雄性小鼠更容易发展为肺动脉高压。高氧暴露诱导了小鼠肺部以及从新生鼠和人类胎儿供体分离的培养肺微血管内皮细胞（LMVEC）中的 EndoMT。从雄性供体培养的 LMVEC 中，这种作用比从雌性供体中更强。使用原代小鼠 LMVEC，高氧暴露增加了 Smad2 和 Smad3 的磷酸化，但降低了 Smad7 蛋白水平。用 TGF-β 选择性抑制剂 SB431542 处理可阻断体外高氧诱导的 EndoMT。总之，我们表明新生鼠高氧暴露导致成年后发生血管重塑和肺动脉高压。这与 EndoMT 的增加有关。这些新发现为高氧诱导的血管重塑的机制提供了依据，并为通过靶向 EndoMT 预防 BPD 相关肺动脉高压提供了潜在的方法。2020 年英国和爱尔兰病理学会。约翰威立父子公司出版。
