Vascular endothelial growth factor (VEGF) is important for lung development and function but ideal mouse models are limited to decipher the quantitative relationship between VEGF expression levels and its proper development and pathogenesis. Human SPC promoter has been used to faithfully express genes or cDNAs in the pulmonary epithelium in many transgenic mouse models. In the study, a mouse model of lung-specific and reversible VEGF repression (hspc-rtTR^tg/+/Vegf^tetO/tetO) was generated. Human SPC promoter was used to drive lung-specific rtTR expression, a cDNA coding for doxycycline-regulated transcription repression protein. By crossing with Vegf^tetO/tetO mice, that has tetracycline operator sequences insertion in 5′-UTR region, it allows us to reversibly inhibit lung VEGF transcription from its endogenous level through doxycycline food, water or injection. The tissue-specific inhibition of VEGF is used to mimic abnormal expression levels of VEGF in lung. Reduced VEGF expression in lung is confirmed by quantitative real time PCR and immunoblotting. Lung development and structure was analyzed by histology analysis and found significantly affected under low VEGF. The pulmonary epithelium and alveolarization are found abnormal with swelling alveolar septum and enlargement of air space. Genome-wide gene expression analysis identified that immune activities are involved in the VEGF-regulated lung functions. The transgenic mouse model can be used to mimic human pulmonary diseases. The mouse model confirms the important regulatory roles of epithelial expressed VEGF in lung development and function. This mouse model is valuable for studying VEGF-regulated lung development, pathogenesis and drug screening under low VEGF expression.

血管内皮生长因子 (VEGF) 对肺发育和功能很重要，但理想的小鼠模型仅限于破译 VEGF 表达水平与其正常发育和发病机制之间的定量关系。在许多转基因小鼠模型中，人类 SPC 启动子已被用于在肺上皮细胞中忠实地表达基因或 cDNA。在这项研究中，产生了肺特异性和可逆 VEGF 抑制的小鼠模型 ( hspc - rtTR ^{tg/ +} / Vegf ^tetO/tetO )。人类 SPC 启动子用于驱动肺特异性 rtTR 表达，这是一种编码多西环素调节转录抑制蛋白的 cDNA。通过与Vegf ^tetO/tetO交叉在 5'-UTR 区域插入四环素操纵基因序列的小鼠，它允许我们通过强力霉素食物、水或注射剂从其内源性水平可逆地抑制肺 VEGF 转录。VEGF 的组织特异性抑制用于模拟肺中 VEGF 的异常表达水平。通过定量实时 PCR 和免疫印迹证实肺中 VEGF 表达降低。通过组织学分析对肺发育和结构进行分析，发现在低VEGF下显着影响。肺上皮和肺泡形成异常，肺泡间隔肿胀，气腔扩大。全基因组基因表达分析确定免疫活动与 VEGF 调节的肺功能有关。转基因小鼠模型可用于模拟人类肺部疾病。小鼠模型证实了上皮表达的 VEGF 在肺发育和功能中的重要调节作用。该小鼠模型对于研究 VEGF 调节的肺发育、发病机制和低 VEGF 表达下的药物筛选很有价值。