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.
Organisations
Publications
Cureton N
(2017)
Selective Targeting of a Novel Vasodilator to the Uterine Vasculature to Treat Impaired Uteroplacental Perfusion in Pregnancy.
in Theranostics
Desforges M
(2015)
Elastin-derived peptides stimulate trophoblast migration and invasion: a positive feedback loop to enhance spiral artery remodelling
in MHR: Basic science of reproductive medicine
Desforges M.
(2012)
A role for elastin-derived peptides in human uterine spiral artery remodelling
in INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY
Desforges Michelle
(2011)
ELASTIN-DERIVED PEPTIDES STIMULATE TROPHOBLAST INVASION: A POSITIVE FEEDBACK LOOP TO ENHANCE SPIRAL ARTERY REMODELLING?
in PLACENTA
Desforges Michelle
(2012)
ELASTIN-DERIVED PEPTIDE MEDIATED SIGNALLING IN EXTRAVILLOUS TROPHOBLAST
in PLACENTA
Smith SD
(2016)
Changes in vascular extracellular matrix composition during decidual spiral arteriole remodeling in early human pregnancy.
in Histology and histopathology
| 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 |