Effects of Recombinant Endothelial Growth Factor 121 Therapy on Maternal Vascular Function and Vascular Fetal Programming in a Mouse Model of Preeclampsia
dc.contributor.committeeMember | Saade, George R | |
dc.contributor.committeeMember | Hankins, Gary D | |
dc.contributor.committeeMember | Rudkin, Laura | |
dc.contributor.committeeMember | Freeman, Daniel | |
dc.contributor.committeeMember | Snodgrass, Wayne R | |
dc.contributor.committeeMember | Blackwell, Sean | |
dc.creator | Mateus-nino, Julio 1971- | |
dc.date.accessioned | 2016-11-01T18:11:45Z | |
dc.date.available | 2016-11-01T18:11:45Z | |
dc.date.created | 2011-08 | |
dc.date.submitted | August 2011 | |
dc.date.updated | 2016-11-01T18:11:45Z | |
dc.description.abstract | Preeclampsia is believed to be caused by an imbalance between placental perfusion and placental metabolic needs. The hypoxic placenta releases factors into the maternal circulation, causing dysfunctional maternal endothelium, and resulting in blood pressure increase and end organ damage. Pregnancies destined to develop preeclampsia have altered cardiovascular adaptations which results in endothelial dysfunction, and abnormal placental perfusion. Various angiogenic growth factors, such as the vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), have been shown to play an important role in the vascular physiologic changes occurring during pregnancy; therefore, inhibition of their function is believed to be one of the mechanisms leading to preeclampsia. One of the inhibitors of these angiogenic factors is the circulating form of the VEGF receptor 1, or soluble fms-like tyrosine kinase1 (sFlt-1). The soluble Flt-1 is generated by differential mRNA splicing of VEGF receptor 1. Soluble Flt-1 acts as a potent antagonist of VEGF and PlGF by preventing them from binding to their endothelial cell receptor, VEGFR-1 and VEGFR-2. Recently, we validated a mouse model of preeclampsia induced by overexpression of sFlt-1 through injection of the adenovirus. Given its key role in preeclampsia, sFlt-1 has turned into a new target for drugs therapies. Clinical and animals studies have shown that exogenous VEGF is useful in vascular conditions with endothelial dysfunction and altered angiogenesis. Our study examined the efficacy of VEGF-121, a freely diffusible protein, in improving maternal vascular dysfunction and altered fetal vascular programming in the preeclampsia-like pregnant mice overexpressing sFlt-1. The therapy had beneficial effects including inhibition of circulating sFlt-1, reduction of maternal blood pressure, amelioration of endothelial function, and diminishment of placental hypoxia. In addition, VEGF-121 enhanced intrauterine fetal growth and prevented hypertension and endothelial dysfunction in the adult male offspring. Our findings underscore the importance of angiogenic factors in mediating vascular adaptations in pregnancy and in regulating fetal vascular development. Targeting the VEGF signaling pathway may play a role in the treatment of preeclampsia and thereby this innovative therapy modality needs further to be tested in clinical studies. | |
dc.format.mimetype | application/pdf | |
dc.identifier.uri | http://hdl.handle.net/2152.3/770 | |
dc.subject | Preeclampsia | |
dc.subject | VEGF | |
dc.subject | sFlt-1 | |
dc.subject | Angiogenic Factors | |
dc.subject | Endothelial Dysfunction | |
dc.subject | Fetal Programming | |
dc.title | Effects of Recombinant Endothelial Growth Factor 121 Therapy on Maternal Vascular Function and Vascular Fetal Programming in a Mouse Model of Preeclampsia | |
dc.type | Thesis | |
dc.type.material | text | |
thesis.degree.department | Population Health Sciences | |
thesis.degree.discipline | Population Health Sciences | |
thesis.degree.grantor | The University of Texas Medical Branch at Galveston | |
thesis.degree.level | Doctoral | |
thesis.degree.name | Clinical Science (Doctoral) |