Rationale: Pulmonary angiogenesis is a key driver of alveolarization. Our prior studies showed that nuclear factor kappa-B (NFlower case Greek kappaB) promotes pulmonary angiogenesis during early alveolarization. However, the mechanisms regulating temporal-specific NFlower case Greek kappaB activation in the pulmonary vasculature are unknown. Objectives: To identify mechanisms that activate pro-angiogenic NFlower case Greek kappaB signaling in the developing pulmonary vasculature. Methods: Proteomic analysis of the lung secretome was performed using 2D-DIGE. NFlower case Greek kappaB activation and angiogenic function was assessed in primary pulmonary endothelial cells (PEC) and TGFBI-regulated genes identified using RNA-sequencing. Alveolarization and pulmonary angiogenesis was assessed in WT and TGFBI null mice exposed to normoxia or hyperoxia. Lung TGFBI expression was determined in premature lambs supported by invasive and noninvasive respiratory support. Measurements and Main Results: Secreted factors from the early alveolar, but not the late alveolar or adult lung, promoted proliferation and migration in quiescent, adult PEC. Proteomic analysis identified transforming growth factor beta-induced protein (TGFBI) as a protein highly expressed by myofibroblasts in the early alveolar lung that promoted PEC migration by activating NFlower case Greek kappaB via lower case Greek alphavlower case Greek beta3 integrins. RNA-sequencing identified Csf3 as a TGFBI-regulated gene that enhances nitric oxide production in PEC. Loss of TGFBI in mice exaggerated the impaired pulmonary angiogenesis induced by chronic hyperoxia, and TGFBI expression was disrupted in premature lambs with impaired alveolarization. Conclusions: Our studies identify TGFBI as a developmentally-regulated protein that promotes NFkB-mediated angiogenesis during early alveolarization by enhancing nitric oxide production. We speculate that dysregulation of TGFBI expression may contribute to diseases marked by impaired alveolar and vascular growth.

中文翻译：

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转化生长因子诱导蛋白的发育表达促进产后肺发育过程中NF-κB介导的血管生成。

理由：肺血管生成是肺泡化的关键驱动力。我们以前的研究表明，核因子κB（NFlower案希腊语κB）在早期肺泡形成过程中促进肺血管生成。但是，尚不清楚调节肺血管系统中特定于时间的NFlower病例Greek kappaB激活的机制。目的：确定在发展中的肺脉管系统中激活促血管生成性NFlower病例希腊语κB信号转导的机制。方法：使用2D-DIGE对肺分泌蛋白进行蛋白质组学分析。在NFlower病例中，在原发性肺内皮细胞（PEC）和TGFBI调控的基因中使用RNA测序鉴定了希腊kappaB的激活和血管生成功能。在暴露于常氧或高氧的WT和TGFBI无小鼠中评估肺泡化和肺血管生成。在有创和无创呼吸支持下，在早产羔羊中测定了肺TGFBI表达。测量和主要结果：早期肺泡而非晚期肺泡或成年肺中的分泌因子促进了静态成年PEC的增殖和迁移。蛋白质组学分析确定了转化生长因子β诱导蛋白（TGFBI）是早期肺泡肺中成纤维细胞高度表达的蛋白，该蛋白通过小写希腊字母alphavlower小写希腊beta3整合素激活NFlower小写希腊kappaB来促进PEC迁移。RNA测序确定Csf3为TGFBI调控的基因，可增强PEC中一氧化氮的产生。小鼠中TGFBI的丢失夸大了慢性高氧引起的肺血管生成受损，TGFBI表达在早产羔羊中受到肺泡化作用的破坏。结论：我们的研究确定TGFBI是一种发育受调节的蛋白，可通过增强一氧化氮的产生促进早期肺泡化过程中NFkB介导的血管生成。我们推测，TGFBI表达失调可能导致以肺泡和血管生长受损为特征的疾病。