Item – Theses Canada

​
OCLC number
1019464062
Link(s) to full text
LAC copy
Author
Gregory, Allison.
Title
Structural and Functional Characteristics of a Soluble Form of Endoglin in the Context of Preeclampsia.
Degree
M. Sc. -- University of Toronto, 2011
Publisher
Ottawa : Library and Archives Canada = Bibliothèque et Archives Canada, 2012.
Description
1 online resource
Notes
Includes bibliographical references.
Abstract
<?Pub Inc> Endoglin is an auxiliary receptor for ligands of TGF-[beta] receptor superfamily. It is an integral membrane protein highly expressed in the vascular endothelium. It is also present in the placental syncytiotrophoblast layer, and up-regulated during pregnancy. The expression of membrane endoglin (mEng) is further increased in the placenta during preeclampsia, a pregnancy-specific hypertensive syndrome. We hypothesize that the soluble form of endoglin (sEng) released from the placenta leads to endothelial dysfunction and hypertension by disrupting normal BMP-9 signaling. We first analyze the ligand specificity of mEng by comparing endoglin-deficient and normal endothelial cells. We show that the presence of mEng at the cell surface inhibits TGF-[beta]1, BMP-2, and BMP-7 induced Smad1,5,8 phosphorylation while potentiating BMP-9 induced signaling. sEng has been shown to be elevated in the sera of preeclamptic women several weeks before the onset of clinical signs of preeclampsia and is postulated to interfere with endothelial cell function. We engineered a soluble form of sEng for both structural and functional studies. We show that sEng binds to BMP-9 with a 2 nM affinity, much higher than observed for other ligands. We also show that sEng can compete for BMP-9 binding to endothelial cells, resulting in inhibition of downstream Smad1,5,8 phosphorylation. Our results suggest that sEng is contributing to endothelial dysfunction and hypertension by dysregulating BMP-9 signaling in the maternal vasculature.
ISBN
9780494768136
0494768134
9780494768136