| dc.description.abstract | Current thinking suggests that preeclampsia is associated with activation of the
maternal vascular endothelium in response to factors released from the placenta due to
placental hypoxia. Failure of physiological modification of spiral arteries due to
impaired trophoblast invasion results in a several-fold increase in the risk of
developing pre-eclampsia and/or (IUGR). The defect behind impaired trophoblast
invasion is not fully explained and the aetiological factor(s) linked with the
development of pre-eclampsia, compared to normotensive IUGR, is not known. In
this thesis, I examined placental and serum levels of fms-like tyrosine kinase I (sFltl)
and placental growth factor (PIGF), as mediators of angiogenesis, and Fas and FasL,
as mediators of apoptosis, in three groups; preeclampsia, normotensive IUGR and
controls who had abnormal mid-trimester uterine artery Doppler.
Uterine artery Doppler flows were examined in 553 women at 24 weeks. 97 of them
had abnormal uterine artery Doppler flow and were enrolled in this study. 86 women
were followed up; among them eight women developed preeclampsia and seven
developed normotensive IUGR. Umbilical artery Doppler examination 24 hours
before delivery in both groups, showed significantly lowered resistance indices in the
preeclampsia compared to the normotensive IUGR group.
I examined placental and serum levels of fms-like tyrosine kinase I (FIt I) and
Placental Growth Factor (PIGF) in three groups. Soluble FItI acts as an antagonist for
both Vascular Endothelial Growth Factor (VEGF) and PIGF. Placental FIt 1 and serum
sFlt 1 were higher and serum PIGF was lower in the preeclampsia group compared to
the other two groups. This could be responsible for the systemic manifestations of
preeclampsia. This dysregulation in serum sFltl and PIGF was found as early as 24
weeks in pregnancies with abnormal uterine artery Doppler examination. The
normotensive IUGR group had significantly elevated serum sFlU compared to
controls. This could be due to an element of placental hypoxia in the IUGR group.
To investigate the in-vivo effect of sFltl on impaired placental angiogenesis and
trophoblast invasion, I examined the correlations between uterine artery Doppler
resistance indices and serum sFIU and PIGF at 24 weeks. Significant correlations
were found between these markers and uterine artery Doppler pulsatility index (pn
and resistance index (Rn on both the placental and non-placental sides at 24 weeks.
Fas and Fas ligand (FasL) are membrane proteins that mediate cellular apoptosis, and
recently were related to cellular growth and migration. Using western blotting and
immunohistochemistry, placental expression of Fas (western blotting) and (FasL)
(immunohistochemistry) was assessed in the three study groups. No differences in
placental Fas or Fas ligand were found between the groups. In addition, serum levels
of Fas and FasL were measured at 24 weeks and within 24 hours of delivery in the
same groups. Serum Fas was not different between the three study groups at 24 weeks
and within 24 hours of delivery. Serum FasL was below the kit's detection threshold
in the samples studied.
In conclusion, placental FlU and its soluble form sFltl seem to play an important role
in the pathophysiology of preeclampsia. In addition, sFltl correlated positively with
the severity of impaired trophoblast invasion and could playa central role in blocking
placental angiogenesis in these pregnancies. This needs further evaluation. Fas and
FasL do not seem to have a role In impaired placentation and development of
preeclampsia and IUGR. | en_US |
