Biology Reference
In-Depth Information
Chapter 11
Pregnancy Induced Reprogramming
of Endothelial Function in Response to ATP:
Evidence for Post Receptor Ca
2+
Signaling
Plasticity
FuXian Yi, Derek S. Boeldt, and Ian M. Bird
Abstract
Studies of uterine artery endothelial cells in primary culture (UAEC)
have shown that ATP stimulates eNOS activation in cells obtained during late
pregnancy (P-UAEC) to a greater extent that in cells obtained in the nonpregnant
state (NP-UAEC). While ATP-stimulated intracellular free Ca
2+
([Ca
2+
]i) in the ini-
tial peak is similar, P-UAEC show a greater sustained phase that underlies a greater
and more prolonged eNOS activation in uterine artery endothelium. While P2X
and P2Y receptors are both present in UAEC, a number of studies suggest P2Y2
mediates the Ca
2+
and eNOS responses to ATP. After the initial [Ca
2+
]i peak, the
sustained phase is a form of Capacitative Ca
2+
Entry (CCE) which is dependent on
extracellular Ca
2+
and fully blocked (along with the initial peak) by blockers of IP3
generation (U73122) or IP3 action (2-APB). One form of channel associated with
CCE in an IP3 dependent fashion is the transient receptor potential cation chan-
nels (TRPC) family, and particularly TRPC3 and 6. While TRPC3 and 6, and many
other proteins involved in the responses (P2Y2, Gq, IP3R1/2/3 and PLC beta3) are
all expressed in UAEC, none are expressed at different levels in NP- vs. P-UAEC.
Nonetheless, immunoprecipitation studies still show that functional association of
TRPC3 with IP3R2 in response to ATP in P-UAEC far exceeds that observed in
NP-UAEC. We have found that the pregnancy enhanced sustained [Ca
2+
]i response
requires a pregnancy enhanced cell-cell communication via connexin 43 (CX43)
Gap junctions. We have also found that the prolonged [Ca
2+
]i response observed in
UAEC is buffered by the mitochondria in a manner further enhanced by pregnancy.
We conclude that pregnancy adaptation of UAEC function involves reprogram-
ming at multiple levels of cell signaling to prolong [Ca
2+
]i responses and cell-cell
synchronization, thereby greatly enhancing eNOS activation.
Keywords
Uterine artery
·
Endothelial
·
UAEC
·
Programming
·
Adaptation
·
Ca
2+
Pregnancy
·
·
eNOS
·
NO
·
P2Y2
·
IP3 (inositol 1,4,5-trisphosphate)
·
IP3-R
B
I.M. Bird (
)
Perinatal Research Laboratories, Department OBGyn, University Wisconsin School Medicine
and Public Health, 7E Meriter Hospital, 202 South Park Street, Madison, WI 53715, USA
e-mail: imbird@wisc.edu
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