Maternal apelin physiology during rat pregnancy: the role of the placenta.
OBJECTIVE
Apelin is a multifunctional peptide which is catabolized by the angiotensin-converting enzyme-related carboxypeptidase-2 (ACE2). The peptide is well known for its hemodynamic effects and its role in energy and fluid homeostasis. Pregnancy is a state of dramatically altered maternal hemodynamics and metabolism, but the role of apelin is unknown. To gain further insight in apelin physiology, we investigated relative tissue expression, plasma clearance and metabolic pathways of apelin in pregnant rats.


METHODS
We measured maternal plasma apelin levels throughout normal rat gestation and examined relative apelin gene expression in several tissues, including the placenta. We documented apelin clearance using radiolabeled apelin and assessed maternal plasma levels in rats that underwent surgical reduction of the fetoplacental mass, thereby further examining the role of the placenta in apelin clearance. Finally, we localized apelin and ACE2 in the placenta and mesometrial triangle using immunohistochemistry.


RESULTS
Maternal apelin plasma concentrations dropped by 50% between mid- and late gestation. Apelin expression was comparable between non-pregnant and late-pregnant rats in non-reproductive tissues. The placenta showed low apelin gene expression compared to brain tissue. Apelin clearance was enhanced in term gestation as evidenced by a steeper decline of the slow phase of the elimination curve of radiolabeled apelin. Compared to sham-operated dams, maternal plasma apelin was raised by 23% in late-pregnant rats in which half of the fetoplacental units were removed at day 16 of gestation. ACE2 mRNA expression was detectable in late- but not mid-pregnancy placental tissue; immunohistochemically, ACE2 was primarily localized in the smooth muscle layer of fetal arterioles in the labyrinth.


CONCLUSIONS
Maternal circulating apelin drops considerably between mid- and late- pregnancy owing to faster clearance. The current data suggest a role for placental ACE2 in the accelerated apelin metabolism.
Van Mieghem
T
T
Department of Obstetrics and Gynecology, Health Campus Gasthuisberg, Katholieke Universiteit Leuven, Herestraat 49, Leuven, Belgium. tim.vanmieghem@uzleuven.be
van Bree
R
R
Van Herck
E
E
Pijnenborg
R
R
Deprest
J
J
Verhaeghe
J
J
D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D000073861:Apelin; D002352:Carrier Proteins / Q000097:blood* / Q000493:pharmacokinetics; D005260:Female; D006706:Homeostasis; D036341:Intercellular Signaling Peptides and Proteins; D008657:Metabolic Clearance Rate; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy / Q000097:blood*; D018607:Pregnancy Reduction, Multifetal; D051381:Rats; D017207:Rats, Sprague-Dawley
D000073861:Apelin; C498579:Apln protein, rat; D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2