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

 描述（由申请人提供）：先天性畸形发生在高达10%的婴儿出生的糖尿病妇女。虽然母体糖尿病的高血糖症靶向多个器官，但胚胎血管系统是第一个发育的系统，也是最脆弱的。糖尿病诱导胚胎血管病变，导致胚胎死亡或神经管缺陷（NTD）。母体糖尿病诱导血管Flk 1+祖细胞减少和凋亡，并减少血岛数量，导致异常血管发生。我们的初步数据表明，纠正改变血管信号和血管病变导致减少NTD的形成。我们假设母体糖尿病诱导的DNA高甲基化导致FGF 2和BMP 4下调，从而增强VEGFR 1表达，导致VEGFR 2信号转导受损，并且这些事件伴随导致血管Flk 1+祖细胞丢失和血管病变。通过恢复FGF 2或BMP 4表达来减轻血管病变，缓解细胞应激并阻断神经上皮细胞中的JNK 1/2和凋亡，从而减少NTD形成。恢复FGF 2和BMP 4表达可预防血管病变和NTD。目的1将确定DNA超甲基化在血管基因沉默中的作用，从而导致血管病变和NTD形成。我们的工作假设是，DNA超甲基化有助于血管基因沉默，而糖尿病胚胎病的主要致病因素，氧化应激是负责DNA超甲基化和血管基因沉默。目的2将确定FGF 2减少诱导的血管病变是否导致NTD形成。我们假设糖尿病抑制的FGF 2表达导致Flk 1+祖细胞丢失和VEGFR 2信号传导受损，导致血管病变和随后的NTD形成。目的3将确定恢复血管中BMP 4表达是否改善血管病变和NTD形成。我们的假设是BMP 4减少介导母体糖尿病对血管发生的致病作用，导致NTD形成。我们的申请研究了新的母体糖尿病在早期发育阶段改变的血管信号传导，证明了一个新的概念，即改变的血管信号传导和由此产生的血管病变导致NTD，并通过提出血管Flk 1+祖细胞活力和血岛形成作为这种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.