Role of Igf2 in placental angiogenesis and effects on cardiovascular function and metabolism
Supervisor, Miguel Constância (IMS); Co-Supervisor, Dr Kristian Franze (PDN)
An extensive capillary network with a large surface area for exchange is vital for fetal growth and
survival. This network expands dramatically in late gestation in both mouse and human placentas
and serves to increase the exchange capacity during the period of greatest fetal growth. Fetal
growth restriction in humans is often associated with reduced placental vascularization. The genetic
factors that contribute to the development of the fetoplacental vasculature in late gestation are
largely unknown.
Recently, we found that IGF2 is a major modulator of placental vascular growth in gestation
(unpublished). The expansion of the fetal capillary network in late gestation does not occur in mice
that lack IGF2 derived from fetal tissues and the fetal endothelium in the placenta. This is associated
with a defect in endothelial cell proliferation in the placenta, ultimately resulting in a loss of ~50% of
endothelial cells over other cell types. Modulators of angiogenesis, such as angiopoietins and Notch
pathway members are de-regulated in this model.
The aim of this studentship is to fully understand the precise mechanisms by which IGF2 controls
placental vascular growth. For that purpose you will: a) manipulate levels of Igf2 (i.e. deletion and
overexpression) in the fetal endothelium of the placenta using a combination of genetic models, e.g.
Tek-Cre, H19 DMR, Igf2 and Igf2r conditional knock-outs; b) perform RNA Seq studies in FACS sorted
endothelial cells in these diverse models with the aim of identifying downstream pathways; c)
measure blood flow by Doppler and the impact of mechanical stimuli (shear stress) in cultured
endothelial cells derived from genetically manipulated mice; d) assess the consequences of impaired
vascular growth of the placenta on fetal growth, vascular and heart function, and metabolism
throughout the life course.
Insights obtained from this project are expected to be highly relevant to a variety of crossdisciplinary fields of research ranging from trophoblast biology, angiogenesis, mechanotransduction
and developmental programming of adult disease.
The Constancia lab is internationally renowned for their work on Igf2 in placental and fetal
physiology (see references 1 to 3); The Franze lab is a world-leader in the field of
mechanotransduction.
Rotation 1 – Constancia lab: endothelial-specific genetic models of Igf2 during gestation; in vivo
physiological assays and RNA-Seq studies
Rotation 2 – Franze lab: shear stress studies in endothelial cells
1. Constância M et al. (2002) Nature 417:945-8.
2. Constância M et al. (2004) Nature 432:53-7.
3. Constância M et al. (2005) Proc Natl Acad Sci USA 102:19219-24.