The Role of Endogenous Vascular Protection Factors in Preeclampsia

Lead Research Organisation: Aston University
Department Name: Sch of Life and Health Sciences

Abstract

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Technical Summary

Preeclampsia (PE) is a systemic endothelial disease defined clinically as hypertension and proteinuria after 20 weeks gestation. PE involves oxidative stress, dysregulation of placental angiogenesis including the release of soluble anti-angiogenic factors that induce systemic endothelial dysfunction. Little attention has been focussed on endogenous vascular protective factors that may inhibit anti-angiogenic factors such as soluble Flt-1 (sFlt-1; a VEGF antagonist) and soluble endoglin (sEng) that are elevated in preeclampsia. This programme will address the central hypothesis that preeclampsia is the result of a perturbation(s) in the vascular protective factors such as the important cytoprotective and anti-inflammatory enzyme, heme oxygenase-1 (HO-1), Thioredoxin reductase-1 (TrxR) and glutathione peroxidase-1 (Gpx), which function to tightly regulate pro- (Vascular endothelial growth factor-A (VEGF) / endothelial nitric oxide (NO) synthase (eNOS) and anti-angiogenic (sFlt-1 / sEng) factors possibly under the control of the phosphoinositide 3-kinase (PI 3-kinase) / Akt pathway. We propose that the HO/TrxR/GpX via PI 3-kinase /Akt pathways are defective in preeclampsia resulting in increased oxidative stress and exacerbated inflammation leading to the aberrant expression of anti-angiogenic factors (sFlt-1 / sEng) in the placenta. This hypothesis will be examined using three experimental systems (i) primary trophoblast and endothelial cell cultures, (ii) a human placental villous explant model and (iii) two transgenic mouse models of preeclampsia. The mechanism by which HO-1 modulates sFlt-1 and sEng expression mediated by pro-inflammatory cytokines (TNF-alpha, IL-1beta, IFN-gamma) and growth factors (VEGF, Ang-II) will be determined by manipulating the PI 3-kinase/PDK-1/Akt, phospholipase C-gamma1 and protein kinase C signal transduction pathways in these systems. This will be achieved by selective RNAi-mediated gene knockdown or over-expression of wild-type and dominant-negative / constitutively active mutants of the appropriate signalling proteins using adenoviral vectors. Understanding the mechanisms that reduce the prevalence of oxidative stress, inflammatory and anti-angiogenic mediators in preeclampsia may prolong pregnancy, prevent premature delivery, and protect the mother post-partum from persistent endothelial cell activation, which increases her predisposition to cardiovascular disease.

Publications

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Ahmed A (2011) Multiple roles of angiopoietins in atherogenesis. in Current opinion in lipidology

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Bergmann A (2010) Reduction of circulating soluble Flt-1 alleviates preeclampsia-like symptoms in a mouse model. in Journal of cellular and molecular medicine

 
Description BHF Research Grant
Amount £500,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2010 
End 06/2013
 
Description India-UK Scientific Seminars
Amount £10,000 (GBP)
Organisation The Royal Society 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2013 
End 03/2014
 
Title PreDict 
Description We have identified potentially a new biomarker using our mouse model, which we are planing to test in our human population samples. 
Type Of Material Model of mechanisms or symptoms - human 
Provided To Others? No  
Impact Too early to talk about it as its too preliminary. 
 
Title VEGFR1:VEGFR2 selective ligand 
Description Generated a synthetic ligand that binds specifically to heterodimers of VEGF receptor-1 (VEGFR-1) and VEGFR-2 we have called VEGFR1-2. The dimeric ligand comprises one VEGFR-2-specific monomer (VEGF-E) and a VEGFR-1-specific monomer (PlGF-1) used to study endothelial cell homeostasis. 
Type Of Material Technology assay or reagent 
Year Produced 2012 
Provided To Others? Yes  
Impact Other research group recieved MRC funding to work further on this project. 
 
Title adenovirus for specific enzymes under investigation 
Description generated virus for overexpression of key enzymes under investigation 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Publication in Circulation and led to patent application. 
 
Description Stuart Egginton 
Organisation University of Birmingham
Department College of Medical and Dental Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution I have provided the manpower and transgenic animals, which has initiated a study to help Dr Egginton develop new line of research using molecular approach. We will get several publications together and hope to apply for a MRC partnership grant.
Collaborator Contribution Dr Stuart Egginton has helped my group learn about in vivo physiological measurements in mice.
Impact Its too early to have output that is quantifiable.
Start Year 2009
 
Title StAmP 
Description Statins for use in Preeclampsia 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2008
Development Status Under active development/distribution
Impact World's first RCT underway. - StAmP. 
 
Company Name MIRZYME THERAPEUTICS LIMITED 
Description MirZyme Therapeutics is an innovative biopharmaceutical company that focuses on the development and commercialisation of diagnostics and drugs for women with pregnancy complications, specifically preeclampsia. 
Year Established 2016 
Impact Inward investment
Website https://www.mirzyme.com
 
Description 6th International Conference Heme Oxygenase, Miami, Florida 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact 6th International Conference Heme Oxygenase, Miami, Florida

Invited to write a review for leading Journal.
Year(s) Of Engagement Activity 2009
 
Description Biochemical Society - Molecular and Cellular Mechanisms 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Symposium on Angiogenesis

Invited to write a review and offers of collaboration.
Year(s) Of Engagement Activity 2009
 
Description ISSHIP 15th World Congress, Washington 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact 15th World Congress held in Washington by International Society for Hypertension in Pregnancy.

Awareness of our work
Year(s) Of Engagement Activity 2008