Biology Reference
In-Depth Information
11.10 Reprogramming of the UA Endothelial Cells Also Occurs
at the Level of the Mitochondria
Discovery that pregnancy control of Gap junction communication is the means by
which the potential for interaction of IP3-R with TRPC3 is regulated is clearly
a substantial advance, yet there are clearly other factors involved in pregnancy
adaptation of UAEC cell signaling. It is apparent in a number of cells that the
mitochondria can 'communicate' with the ER and influence its ability to respond
to agonists, and recent evidence suggest this may occur in UAEC. Treatment of
the UAEC with carbonyl cyanide m-chloro phenyl hydrozone (CCCP) to inhibit
mitochondrial function limits the increase in [Ca
2+
]i in response to Thapsigargin
or ATP [35]. This effect, however, was not due to a collapse of ATP levels
within the cell, at least in the time period studied. This effect was also not due
to a change in mitochondrial Ca
2+
uptake. Of particular relevance here, the P-
UAEC are more resistant to this effect of CCCP on [Ca
2+
]i than NP-UAEC,
suggesting that pregnancy is perhaps altering mitochondrial function itself. This
is intriguing and the importance of this functional adaptation to pregnancy may
indeed be substantial, given that families with a heritable disorder of mitochon-
drial function are also seen to display preeclampsia like symptoms during pregnancy
[26, 32].
11.11 Future Studies
Given the evidence that CX43 is phosphorylated in UAEC, further study of the
endocrine events that result in changes in permeability of CX43 through phospho-
rylation are clearly warranted. It will be no surprise that these studies are ongoing in
our laboratory at this time. Likewise the ability to directly image NO in
individual
cells of the intact UA endothelium while still attached to the vessel has now been
achieved and the examination of [Ca
2+
]i bursts and synchronization of endothelial
cell function is underway ex vivo. A third area of interest is the question of mito-
chondrial adaptation in pregnancy. While it is clear the mitochondria can effect the
[Ca
2+
]i response to agonists, the exact mechanisms remains unknown. Nonetheless
it is noteworthy that TNF-alpha, known to be elevated in preeclampsia, is capable
of damaging UAEC through excess reactive oxygen species generation (Yi, unpub-
lished) as expected. Further studies into the question of whether TNF-alpha impairs
ATP-stimulated [Ca
2+
]i and, if so, if this is mediated through damage to the mito-
chondria is of particular relevance. It is our hope that as such combined studies
further reveal the molecular components of the [Ca
2+
]i signaling pathway in UAEC
and the manner by which pregnancy acts to alter their function, it will become possi-
ble to identify pharmacologic targets for clinical therapy of signaling dysfunction in
pregnancy associated diseases. More specifically, it is already clear that preeclamp-
sia is in part characterized by a failure of the endothelium to adapt its function.
Observations in hand vein endothelial cells [22] and umbilical vein endothelial cells
[29] suggest those subjects with preeclampsia show a blunted [Ca
2+
]i response just
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