Maternal Diabetes-Suppressed Vascular Signaling Induces Vasculopathy and Neural Tube Defects

 描述(由申请人提供)：糖尿病妇女所生婴儿中有高达10%会发生先天性畸形。虽然母体糖尿病的高血糖针对多个器官，但胚胎血管系统是第一个被开发的系统，也是最脆弱的。糖尿病导致胚胎血管病变，导致胚胎死亡或神经管畸形(NTD)。母体糖尿病诱导血管Flk1+祖细胞减少和凋亡，减少血岛数目，导致异常血管生成。我们的初步数据表明，纠正改变的血管信号和血管病变导致NTD的形成减少。我们假设，母亲糖尿病引起的DNA高甲基化导致FGF2和BMP4的下调，从而增强VEGFR1的表达，导致VEGFR2信号受损，这些事件伴随着血管Flk1+祖细胞的丧失和血管病变。通过恢复FGF2或BMP4的表达来减少血管病变可以缓解细胞压力，阻断JNK1/2和神经上皮细胞的凋亡，从而减少NTD的形成。恢复FGF2和BMP4的表达可以预防血管病变和NTD。目的1将确定DNA高甲基化在导致血管病变和NTD形成的血管基因沉默中的作用。我们的工作假设是DNA高甲基化导致血管基因沉默，而氧化应激是糖尿病胚胎病变的主要原因，是DNA高甲基化和血管基因沉默的原因。目的2将确定FGF2减少引起的血管病变是否导致NTD的形成。我们假设，糖尿病抑制的FGF2表达导致Flk1+祖细胞丢失和VEGFR2信号受损，导致血管病变和随之而来的NTD形成。目的3将确定恢复BMP4在血管中的表达是否改善血管病变和NTD的形成。我们的假设是，BMP4的减少介导了母体糖尿病对血管生成的致病作用，从而导致NTD的形成。我们的应用研究了早期发育阶段新的母体糖尿病改变的血管信号，证明了一个新的概念，即改变的血管信号和由此产生的血管病变导致NTD，并通过提出血管Flk1+祖细胞活性和血岛形成作为该疾病过程的中心步骤来克服现有的障碍。

 DESCRIPTION (provided by applicant): Congenital malformations occur in up to 10% of babies born to diabetic women. While hyperglycemia of maternal diabetes targets multiple organs, embryonic vasculature is the first system to be developed and is most vulnerable. Diabetes induces embryonic vasculopathy leading to embryonic lethality or neural tube defects (NTD). Maternal diabetes induces the reduction and apoptosis in vascular Flk1+ progenitors and reduces blood island numbers resulting in aberrant vasculogenesis. Our preliminary data suggest that correcting altered vascular signaling and vasculopathy leads to reduced NTD formation. We hypothesize that maternal diabetes-induced DNA hypermethylation causes the downregulation of FGF2 and BMP4, which enhances VEGFR1 expression leading to impaired VEGFR2 signaling, and that these events concomitantly result in vascular Flk1+ progenitor loss and vasculopathy. Reducing vasculopathy by restoring either FGF2 or BMP4 expression relieves cellular stress and blocks JNK1/2 and apoptosis in neuroepithelial cells leading to decreased NTD formation. Restoring both FGF2 and BMP4 expression prevents vasculopathy and NTD. Aim 1 will determine the role of DNA hypermethylation in vascular gene silencing that leads to vasculopathy and NTD formation. Our working hypothesis is that DNA hypermethylation contributes to vascular gene silencing, and that the major causal factor in diabetic embryopathy, oxidative stress is responsible for DNA hypermethylation and vascular gene silencing. Aim 2 will determine whether FGF2 reduction-induced vasculopathy causes NTD formation. We hypothesize that diabetes-suppressed FGF2 expression causes Flk1+ progenitor loss and impaired VEGFR2 signaling leading to vasculopathy and consequent NTD formation. Aim 3 will determine whether restoring BMP4 expression in vasculature ameliorates vasculopathy and NTD formation. Our hypothesis is that BMP4 reduction mediates the pathogenic effect of maternal diabetes on vasculogenesis leading to NTD formation. Our application investigates novel maternal diabetes-altered vascular signaling at early development stages, proves a new concept that altered vascular signaling and resultant vasculopathy cause NTD, and overcomes existing barriers by proposing vascular Flk1+ progenitor viability and blood island formation as central steps in this disease process.