PDF(Pubmed)
Abstract：
Plexiform lesions are a hallmark of pulmonary arterial hypertension (PAH) in humans and are proposed to stem from dysfunctional angioblasts. Broiler chickens (Gallus gallus) are highly susceptible to PAH, with plexiform-like lesions observed in newly hatched individuals. Here, we reported the emergence of plexiform-like lesions in the embryonic lungs of broiler chickens. Lung samples were collected from broiler chickens at embryonic day 20 (E20), hatch, and one-day-old, with PAH-resistant layer chickens as controls. Plexiform lesions consisting of CD133+/vascular endothelial growth factor receptor type-2 (VEGFR-2)+ angioblasts were exclusively observed in broiler embryos and sporadically in layer embryos. Distinct gene profiles of angiogenic factors were observed between the two strains, with impaired VEGF-A/VEGFR-2 signaling correlating with lesion development and reduced arteriogenesis. Pharmaceutical inhibition of VEGFR-2 resulted in enhanced lesion development in layer embryos. Moreover, broiler embryonic lungs displayed increased activation of HIF-1α and nuclear factor erythroid 2-related factor 2 (Nrf2), indicating a hypoxic state. Remarkably, we found a negative correlation between lung Nrf2 activation and VEGF-A and VEGFR-2 expression. In vitro studies indicated that Nrf2 overactivation restricted VEGF signaling in endothelial progenitor cells. The findings from broiler embryos suggest an association between plexiform lesion development and impaired VEGF system due to aberrant activation of Nrf2.
摘要：
丛状病变是人类肺动脉高压（PAH）的标志，被认为源于功能失调的成血管细胞。肉鸡（Gallusgallus）对PAH高度敏感，在新孵化的个体中观察到丛状样病变。这里,我们报道了肉鸡胚胎肺中出现丛状样病变。在胚胎第20天（E20）从肉鸡中收集肺样品，舱口,一天大,以抗PAH蛋鸡为对照。仅在肉鸡胚胎中观察到由CD133/血管内皮生长因子受体2型（VEGFR-2）成血管细胞组成的丛状病变，偶尔在层胚中观察到。在两个菌株之间观察到血管生成因子的不同基因谱，VEGF-A/VEGFR-2信号传导受损，与病变发展和动脉生成减少相关。VEGFR-2的药物抑制导致层胚的病变发育增强。此外，肉鸡胚胎肺显示HIF-1α和核因子类2相关因子2（Nrf2）的激活增加，表明处于缺氧状态。值得注意的是,我们发现肺Nrf2激活与VEGF-A和VEGFR-2表达呈负相关。体外研究表明，Nrf2过度激活限制了内皮祖细胞中的VEGF信号传导。肉鸡胚胎的发现表明，由于Nrf2的异常激活，丛状病变的发展与VEGF系统受损之间存在关联。
