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

母亲糖尿病抑制的血管信号传导导致血管病变和神经管缺陷

基本信息

批准号：
9080869
负责人：
Peixin Yang
金额：
$ 51.97万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9080869
关键词：
Adverse effects Age American Apoptosis BMP4 Binding Blood Island Blood Vessels Cellular Stress Complications of Diabetes Mellitus Congenital Abnormality CpG Islands Cytosine DNA DNA Methylation Data Defect Development Diabetes Mellitus Disease Down-Regulation Embryo Endoderm Epigenetic Process Event Exposure to FGF2 gene Gene Deletion Gene Silencing Health Hydralazine Hyperglycemia Hypermethylation In Situ In Vitro Individual KDR gene MAPK8 gene Mediating Methylation Monitor Mus Neural Tube Defects Neural tube Neuroepithelial Cells Organ Oxidative Stress Pathogenesis Pregnancy in Diabetics Prevention Process Recombinants Role Series Signal Transduction Staging System Testing Therapeutic Intervention Transgenic Mice Vascular Diseases Vascular Endothelial Growth Factor Receptor-1 Woman Work Yolk Sac density diabetic diabetic embryopathy endoplasmic reticulum stress fetal glycemic control inhibitor/antagonist mRNA Expression maternal diabetes novel overexpression prevent progenitor promoter protein expression public health relevance reproductive targeted treatment transcription factor type I and type II diabetes vascular factor vasculogenesis

项目摘要

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.