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Program Abstract
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Presentation Title Matrix Metallopeptidase 12 and the Endovascular Invasive
Trophoblast Lineage
Session Title Poster Session C
Session Poster Session C
Session Day -
Time
7/22/2014 7:00 AM - 9:00 AM
Presentation
Time
7/22/2014 7:00 AM - 7:00 AM
Location DeVos Place - Exhibit Hall C
Presentation
Type
Poster
Authors Wei Cui ; Damayanti Chakraborty ; M.A. Karim Rumi ; Gracy
X. Rosario ; Pramod Dhakal ; Kaiyu Kubota ; Jay L. Vivian ;
Michael J. Soares
Affiliations Department of Pathology & Laboratory Medicine, KUMC,
Kansas City, United States of America; Department of
Pathology and Laboratory Medicine, KUMC, Kansas City,
United States of America; Department of Pathology and
Laboratory Medicine, KUMC, Kansas City, United States of
America; Department of Pathology and Laboratory Medicine,
KUMC, Kansas City, United States of America; Department of
Pathology and Laboratory Medicine, KUMC, Kansas City,
United States of America; Department of Pathology and
Laboratory Medicine, KUMC, Kansas City, United States of
America; Department of Pathology and Laboratory Medicine,
KUMC, Kansas City, United States of America; Department of
Pathology and Laboratory Medicine, KUMC, Kansas City,
United States of America
Abstract Hemochorial placenta develops from coordinated multi-
lineage differentiation of trophoblast cells. Specific
trophoblast cell lineages are organized within the placentation
site to perform specialized functions. The invasive trophoblast
lineage remodels uterine spiral arteries to convert them to
flaccid low resistance vessels, facilitating the flow of nutrients
to the placenta and fetus. Failure of trophoblast invasion and
vascular remodeling is associated with pathological conditions
such as preeclampsia, intrauterine growth restriction, and

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preterm birth. Proteins of the matrix metallopeptidase (MMP)
family are involved in the breakdown of extracellular matrix
in normal physiological processes, including embryonic
development, reproduction, and tissue or vascular
remodeling. Matrix metallopeptidase 12 (MMP12) is a
metalloelastase possessing the capacity to degrade elastin
and modify the structure of arterial blood vessels. MMP12 is
expressed in human trophoblast and is a candidate regulator
of uterine spiral artery remodeling. In this project, we explore
the capacity of the invasive trophoblast lineage to produce
MMP12 and establish a genetic model for investigating
MMP12 actions during the establishment of the hemochorial
placenta. Our initial observation indicating a linkage between
MMP12 and the invasive trophoblast lineage was derived from
DNA microarray analysis of uterine mesometrial
compartments of pregnant rats exposed to atmospheric and
hypoxic environments. Hypoxia stimulates trophoblast cell
invasion into the uterine mesometrial compartment. MMP12
was dramatically upregulated in the hypoxic state and
specifically expressed exclusively in endovascular invasive
trophoblast cells lining uterine spiral arteries. This
observation was effectively modeled in vitro using rat
trophoblast stem cells. MMP12 was dramatically upregulated
during trophoblast differentiation induced by exposure to low
or to mitogen removal. The hypoxia driven response was
hypoxia-inducible factor dependent and associated with
changes in histone H3K9 methylation modifications at the
Mmp12 locus. To explore further the functional importance of
MMP12 in trophoblast invasion, we generated a mutant rat
model using TALEN-mediated genome editing. mRNAs
encoding TALENs targeted to exon 2 of rat Mmp12 were
microinjected into one-cell rat embryos which were then
transferred to pseudopregnant recipients. Of 69 live births,
two founders possessed biallelic Mmp12 mutations and
eleven founders possessed monoallelic or mosaic Mmp12
mutations. The mutations consisted of deletions ranging in
size from 100 bp to 800 bp. Three founders with larger
deletions were backcrossed to wild-type rats and
heterozygous offspring subsequently intercrossed to generate
homozygous Mmp12 mutant rats for further characterization.
In summary, MMP12 is an intriguing extracellular matrix-
modifying enzyme induced during activation of the invasive
trophoblast lineage. The availability of Mmp12 mutant rats
will provide an effective experimental tool for evaluation of
the involvement of MMP12 in uterine spiral artery remodeling
and hemochorial placentation. (Supported by AHA, JSPS, and
KUMC-BRTP postdoctoral fellowships and NIH HD020676)
Topic Category Implantation and Pregnancy—Placental Function