Antenatal maternal hypoxic stress: adaptations of the placental renin-angiotensin system in the mouse.
The stress of Antenatal Maternal Hypoxia (AMH) can lead to a number of physiological and pathological changes in both mother and fetus, changes which can be linked to alterations in placental morphology and gene regulation. Recently, in the Brown Norway rat "model" of placental insufficiency, we reported alterations in placental renin-angiotensin system (RAS) genes. Moreover, AMH can lead to reduced oxygen availability to the fetus, similar to a state of placental insufficiency. Thus, in pregnant mice dams we tested the hypothesis that antenatal maternal hypoxic stress leads to alterations in the placental RAS. These alterations may, in part, account for the phenotypic changes in both pregnant mice dams as well as fetus and adult offspring.


METHODS
Pregnant FVB/NJ mice dams were either maintained as controls, or exposed to 10.5% O(2) for 48 h from 15.5 to 17.5 day post coitum. We then measured placental mRNA and protein expression of several RAS genes (n = 4 to 5; P < 0.05 was considered significant).


RESULTS
In murine placenta: (1) angiotensinogen (AGT) mRNA was undetectable; however, AGT protein was detectable and increased significantly with AMH. (2) In AMH, although renin mRNA was reduced protein expression increased, in association with decreased microRNA (miRNA) 199b, which can lead to increased renin translation. (3) Also in AMH placenta, angiotensin converting enzyme (ACE) -1 mRNA was unaltered; however, protein expression increased significantly, in association with decreased miRNA 27a, which can result in increased ACE-1 translation. (4) In AMH placenta, ACE-2 mRNA was reduced significantly, whereas protein expression was significantly greater, in association with reduced miRNA 429. (5) In AMH placenta, angiotensin II type (AT) -1a receptor mRNA expression was unaltered while AT-1b receptor mRNA was undetectable in both groups. Moreover, AT-1 receptor protein expression was unchanged in response to AMH. (6) AT-2 receptor mRNA and proteins were undetectable in both groups.


CONCLUSIONS
The normal murine placenta possesses several components of RAS, and in response to AMH several of these elements undergo important changes. In addition, differential expression of RAS mRNA, miRNA and protein, indicate post-transcriptional regulatory mechanisms involved with hypoxic stress, and necessitate further investigation.
Center for Perinatal Biology, Department of Physiology, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USA.
R
R
Goyal
R
R
Lister
A
A
Leitzke
D
D
Goyal
C P
CP
Gheorghe
L D
LD
Longo
D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D005260:Female; D000860:Hypoxia / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D010920:Placenta / Q000378:metabolism*; D010927:Placental Insufficiency / Q000378:metabolism; D011247:Pregnancy; D011248:Pregnancy Complications / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000235:genetics* / Q000502:physiology
D035683:MicroRNAs; D012333:RNA, Messenger; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2