Pregnancy Induced Reprogramming of Endothelial Function in Response to ATP: Evidence for Post Receptor Ca Signaling Plasticity - Extracellular ATP and Adenosine as Regulators of Endothelial Cell Function - page 192

(IP3 receptor) · Phospholipase C · TRPC · CX43 · Gap junction · Capacitative

entry · Mitochondria · U73122 · 2-APB

11.1 Background

In the nonpregnant state the blood flow to the uterus is low, but as the fetus grows,
uterine blood flow must increase dramatically to match the progressively increasing
demand for nutrients and oxygen [1]. Although growth of new vessels as well as
remodeling of existing vessels during early pregnancy contributes to the increased
flow, the period of greatest increase in flow occurs after the completion of new
vessel growth, so maintenance of vasodilation in existing or newly-developed
vessels is probably crucial. It is now clear from studies of both vessels and isolated
cells that uterine artery (UA) endothelial nitric oxide (NO) and indeed prostacyclin
production by endothelial cells changes in response to growth factors, bradykinin,
ATP, and angiotensin II (AII) which elicit a rise in [Ca 2+ ]i and/or activate kinases
which in turn activate eNOS and indeed cytosolic phospholipase A2 [8, 18]. The
physiologic mechanisms underlying these adaptive responses to pregnancy in UA
are clearly complex and although the subject of intense investigation, still not fully
understood. Nonetheless, the importance is clear given the mounting evidence that
dysfunctional endocrine regulation of endothelial vasodilator production during
pregnancy may directly result in preeclampsia and possibly associated growth
retardation of the fetus [7, 28].
Most early studies of the effects of agonists on UA endothelial function were
assayed indirectly through the use of inhibitors such at L-NAME on vessel myogra-
phy and/or indirect assay of NO action i.e. assay of cGMP (reviewed in [3]). Before
the methods for the isolation of UA endothelial cells and their maintenance in cul-
ture were developed, it was generally assumed that pregnancy-specific increases in
NO production in response to this broad array of agonists related directly to the
increased expression of eNOS observed at this time [20]. Nonetheless evidence for
the ability to remap cell signaling within UA endothelium was implied by further in
vivo studies performed in different physiologic states. While studies of expression
levels of eNOS protein in UA endothelium showed that during the ovarian cycle,
the follicular phase is associated with a marginal increase in eNOS expression and
systemic NO while pregnancy is associated with a far greater increase in both eNOS
protein and systemic NO [21], further analysis of the UA endothelial eNOS levels
and systemic NO ∗ levels (by luminescent measurement of NO after conversion from
nitrate and nitrite) in pregnancies with singleton, twins and triplets showed that UA
endothelial eNOS does not undergo any substantial further increase with number
of offspring while NO ∗ clearly does [21]. Also, in ovarectomized ewes in response
to exogenous steroid, changes in eNOS expression in response to estrogen (E2B)
and progesterone (P4) alone or together are not uniformly paralleled by changes in
systemic NO [27]. While these studies suggest dissociation between eNOS protein
and function in UA endothelium, the use of systemic NO measurements assumes
that uterine NO production is the major determinant of systemic NO ∗ , which may
not always be the case. Other studies by Xiao et al [34], however, were more clear