MMP-12-mediated vascular elastolysis - a potential target for therapeutic intervention in complicated pregnancies

Lead Research Organisation: University of Manchester
Department Name: Medical and Human Sciences

Abstract

Normally, blood flow is controlled by stretchy, elastic fibres in the walls of blood vessels that allow them to become wider or narrower, as required. In pregnancy, the developing baby needs a constant supply of blood, so elastic fibres in the blood vessels of the womb are broken down and the vessels are permanently widened. If this process does not happen, it can cause the baby to be born too small or too early and can make the mother seriously ill. We have identified one of the proteins that controls breakdown of elastic fibres in the womb and we will study different ways to increase its activity. This will lead to development of a treatment to make blood vessels in the womb wider, if the process does not happen naturally.

Technical Summary

During pregnancy, the uterine spiral arteries are remodelled to ensure a constant supply of blood is delivered to the developing placenta at an optimal rate of flow. Breakdown of elastic fibres in the arterial wall is crucial to facilitate a permanent increase in vessel diameter and to abolish maternal vasomotor control. Impaired vascular remodelling is associated with second trimester miscarriage, pre-eclampsia, preterm labour and fetal growth restriction. We have evidence to suggest that elastin breakdown is mediated by trophoblast- and vascular smooth muscle cell-derived matrix metalloproteinase-12 (MMP-12). In this proposal we will: [i] analyse MMP-12 expression and activity in the placentas and spiral arteries obtained from normal and complicated pregnancies, [ii] investigate the regulation of MMP-12 expression and activity by elastin-derived peptides, and [iii] manipulate MMP-12 activity in ex vivo tissue models to promote spiral artery remodelling.

Publications

10 25 50
 
Description MRes in Maternal and Fetal Health
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact New thinking on the origins of disease in pregnancy is transmitted to postgrad students (UK and international) through face-to face teaching and research projects linked to this MRC-funded project.
 
Description DTP PhD studentship
Amount £65,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2012 
End 09/2016
 
Description NowNano DTC
Amount £55,000 (GBP)
Organisation University of Manchester 
Sector Academic/University
Country United Kingdom
Start 09/2012 
End 09/2015
 
Title Assaying trophoblast invasion quantitatively 
Description Image analysis of trophoblasts outgrowing from explanted first trimester placenta 
Type Of Material Technology assay or reagent 
Provided To Others? Yes  
Impact The method is in continuing use in our laboratory. Since we devised the original method for observational studies of trophoblast invasion, many groups have adopted it, in fact it has become a standard protocol in the field. In recent work we have added a new quantification method, it is too early yet to see if this will be widely adopted. 
 
Description LKH-ER 
Organisation University of California, Santa Barbara
Department Department of Molecular, Cellular and Developmental Biology (MCDB)
Country United States 
Sector Academic/University 
PI Contribution LKH spent a year in the laboratory of Prof Erkki Ruoslahti developing methods of targeting drugs to the placental vasculature
Collaborator Contribution It's part of a BBSRC Fellowship Award held by LKH. Peptide targeting technology developed by the lab at UCSB has been transferred here and we anticipate applicaitons in remodelling vessels in the placenta.
Impact pending
Start Year 2010
 
Description PCnano 
Organisation Southmead Hospital
Department Avon Orthopaedic Centre
Country United Kingdom 
Sector Hospitals 
PI Contribution We are studying growth stimulatory soignals delivered by targeted nanomaterials to the placental vasculature
Collaborator Contribution Their expertise in damage signals is iportant in characterising the particles
Impact Nature Nanotehcnology paper MRC project grant 2012
Start Year 2010
 
Description Pleiotrophin 
Organisation University College Cork
Department School of Biochemistry and Cell Biology
Country Ireland 
Sector Academic/University 
PI Contribution Supply of placental bed tissues
Collaborator Contribution Antibodies to pleiotrophin
Impact Expression of pleiotrophin and its receptors in human placenta suggests roles in trophoblast life cycle and angiogenesis. Ball M, Carmody M, Wynne F, Dockery P, Aigner A, Cameron I, Higgins J, Smith SD, Aplin JD, Moore T. Placenta. 2009 Jul;30(7):649-53
Start Year 2007
 
Description Primate tissue 
Organisation University of California, Davis
Department Department of Cell Biology and Human Anatomy
Country United States 
Sector Academic/University 
PI Contribution Studeis of vascular ecm in the uterus
Collaborator Contribution Supply of primate tissues
Impact ongoing
Start Year 2011
 
Description 1st International RHG Congress 'From Debate to Consensus in Reproductive Medicine' 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I gave a talk, How selective is the endometrium? to a group of practitioners leading to a debate about aspects of ther future of ART.
Year(s) Of Engagement Activity 2015
 
Description A level student visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach Regional
Primary Audience Schools
Results and Impact 60 pupils attended a talk and laboratory tour with questions and career related discussion.

College asked for lab visit for A level students and reported enthusiastic response to hospital-based research.
Year(s) Of Engagement Activity 2011
 
Description BBC Breakfast TV interview February 2018 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact BBC Breakfast TV interview February 2018 discussion growth of human eggs in the laboratory.
Year(s) Of Engagement Activity 2008,2018
 
Description British Science week event 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact As part of a large exhibit during British Science Week in Manchester a group of postdocs and postgrad students (including students from our MRes programme in Reproduction and Pregnancy) hosted visits from school students to an interactive display. Groups from different age groups, both primary ad secondary) participated with their teachers. Exhibits aim to explain embryo implantation, what the placenta does, how the fetus grows and how lifestyle can influence pregnancy.
Year(s) Of Engagement Activity 2018
 
Description Community Festival at Manchester University 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The community event links Manchester university to its local and regional community, aiming to communicate the wide range of activities especially in, but not limited to, science and technology as part of its social responsibility agenda. It is widely advertised in local schools and it was especially pleasing to see how many children and parents from diverse communities paid a visit to our pregnancy stand. Our 'Before you were born' stand has about 6 hands-on activities for children of different ages as well as images, information and models for adults.
Year(s) Of Engagement Activity 2017
URL http://www.socialresponsibility.manchester.ac.uk/strategic-priorities/engaging-our-communities/publi...
 
Description Community open days 2015 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Presentations about pregnancy and the placenta with interactive games for children.


Community open day 2015
http://www.engagement.manchester.ac.uk/blog/?tag=science-spectacular
https://www.flickr.com/photos/128754940@N08/albums/72157660915060789

Community open day 2014
http://events.manchester.ac.uk/event/event:y151-huwpe3xd-dga3v6/flsmhs-community-open-day
Year(s) Of Engagement Activity 2014,2015
 
Description Interview with New Scientist about male fertility 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Interview with New Scientist about male fertility, implications of declining sperm counts in the western world
Year(s) Of Engagement Activity 2017
 
Description Interview with The Economist about male fertility 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Interview with New Scientist about male fertility, particularly the lack of focus on male reproduction compared to female
Year(s) Of Engagement Activity 2018
 
Description Media interest including social media 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Our January 2015 paper on a maternal microRNA that inhibits embryo implantation was the subject of a press release. The item ran in the Daily Mail and was picked up by Cosmo, Elle and numerous other national and international outlets. It has become -- so far -- the 4th most talked about paper in social media ever published in J Cell Science.

I got emails from infertile women.
Year(s) Of Engagement Activity 2015
URL http://www.cosmopolitan.com/sex-love/a36075/major-new-study-shows-why-ivf-doesnt-always-work/
 
Description Postgraduate placentology workshop at Queen's University Kingston Ontario 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The Kingston workshop trains postgraduate researchers and stimulates dialogue and networking on the field.

Research collaborations have sprung from this activity.
Year(s) Of Engagement Activity 2013,2014,2015
URL http://www.queensu.ca/workshops/placenta/?q=node/3
 
Description Postgraduate reproductive biologyh workshop, USP, Sao Paulo, Brazil 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Training for postgraduate students, as well as continuing medical education for Ob/Gyn faculty at USP.

Postgraduates with a strong basic science/animal model focus are stimulated to apply their findings to problems in human pregnancy.
Year(s) Of Engagement Activity 2015
 
Description Public engagement event on the placenta 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Our centre ran the annual conference of IFPA, the International Federation of Placenta Associations, in 2017 at GMEX, an exhibition space in central Manchester. On the final afternoon we held (for the first time at these conferences) a public engagement event with researchers giving short talks, an art exhibition about stillbirth, an image competition that the public voted on, and a large 'hands-on' exhibit for children and adults to learn about pregnancy. The session was popular with the general public, especially families, and was also attended by international scientists who were in town for the meeting, including the outgoing and incoming chairs of IFPA, and was noted as providing innovative leadership for other national associations.
Year(s) Of Engagement Activity 2017
URL http://www.ifpa2017.org/public-engagement/
 
Description Radio 4 interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Several members of the Maternal and Fetal Health Centre contributed to a programme on the placenta in the Frontiers series
http://www.bbc.co.uk/programmes/b00nvdgg

N/a
Year(s) Of Engagement Activity 2009
 
Description SMART Masterclass 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact This SMART Masterclass organised by Merck-Serono included my presentation on: 'Beyond stimulation: Markers of receptivity, what are they telling us?'
Year(s) Of Engagement Activity 2015
 
Description STIRMAS (Society of Trainees in Reproductive Medicine ) Scientific Annual Meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact I presented a talk to the Society of Trainees in Reproductive Medicine Scientific Annual Meeting on 23rd October 2015, London on studying implantation in vitro, leading to a general discussion about overcoming the 'bottleneck' of failed implantation.
Year(s) Of Engagement Activity 2015
 
Description School visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Twenty pupils from a local secondary school visited our laboratories and were educated about the role of the placenta in pregnancy. They were also asked to design a new logo for our group, based on the placenta. The designs were displayed in the hospital for several weeks, were voted on by staff and members of the public and the winning design was adopted as the logo for our Placenta clinic.

A new logo for our Placenta clinic, which manages women at high risk of pregnancy complications, was created.
Year(s) Of Engagement Activity 2010
 
Description Science spectacular at Manchester University 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Manchester University scientists devise interactive activities across a wide range of disciplines. The exhibits are open for a full day in the Manchester Museum and adjacent space and the event is widely advertised. Our stand was visited by many families and couples including present and past patients in our infertility and obstetric services. It attracted a lot of interest about early pregnancy, IVF and the start of life.
Year(s) Of Engagement Activity 2017
URL https://www.facebook.com/events/124428648284796/?active_tab=about
 
Description Talk at Fertility 2015, Birmingham 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Talk sparked discussion as the research impacts on clinical practice

After my talk participants discussed the need for higher investment by funding bodies in assisted reproduction.
Year(s) Of Engagement Activity 2015
URL http://www.fertility2015.org/
 
Description Talk at Meeting: Best of ESRHE and ASRM, New York, March 2015 
Form Of Engagement Activity Scientific meeting (conference/symposium etc.)
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Lots of discussion afterwards

This work is contributing to an increased emphasis on improved endometrial receptivity in IVF-embryo transfer.
Year(s) Of Engagement Activity 2015
URL http://www.asrm.org/uploadedFiles/ASRM_Content/Events/2015_Best_of_ESHRE_and_ASRM/Best_ESHRE-ASRM201...
 
Description Workshop on implantation for trainee embryologists 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact I acted as an outside expert to work with the trainee embryologists on the topic of implantation and endometrial receptivity.
Year(s) Of Engagement Activity 2016,2017,2018