Contribution of angiogenic factors in a rat model of pre-eclampsia.
OBJECTIVE
Pre-eclampsia is a disorder that results in significant feto-maternal complications with yet no definitive pharmacologic intervention. One postulated etiologic mechanism is an imbalance between circulating pro-angiogenic and anti-angiogenic factors. We investigated these factors sequentially throughout pregnancy (19-21 days) in our rat model of pre-eclampsia, which involves the imposition of excessive volume expansion.


METHODS
We evaluated the status of the pro-angiogenic and anti-angiogenic factors at the following time points: 3-5, 7-10 and 17-20 days of gestation.


RESULTS
We have previously determined that the urinary excretion of the circulating bufodienolide, marinobufagenin, is elevated at the 3- to 5-day time period, prior to the advent of hypertension and proteinuria. At 3-5 days of pregnancy, there was no evidence of angiogenic imbalance in the normal pregnant (NP) and 'pre-eclamptic' (PDS) rats. At the 7- to 10-day time point, plasma PlGF was greater in the NP rats than in the PDS group (p < 0.05). The plasma sFlt-1/PlGF ratio in the PDS animals was greater than that in the NP rats (p < 0.05). The placental sFlt-1 and sFlt-1/PlGF ratio were greater in the PDS rats than in NP rats (p < 0.05). These changes were also present at the 17- to 20-day time point in both plasma and placenta. The administration of resibufogenin, an antagonist of marinobufagenin, early in pregnancy, prevented angiogenic imbalance.


CONCLUSIONS
We conclude that angiogenic imbalance plays a role in the pathogenesis of pre-eclampsia in this rat model. Furthermore, the earliest event in the pathogenetic sequence appears to be the secretion and elaboration of marinobufagenin.
Agunanne
E E
EE
Department of Medicine, Texas A&M Health Science Center/Scott & White, Temple, USA.
Uddin
M N
MN
Horvat
D
D
Puschett
J B
JB
D000704:Analysis of Variance; D042501:Angiogenic Proteins / Q000097:blood*; D000818:Animals; D001794:Blood Pressure; D002018:Bufanolides / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000097:blood*; D003404:Creatinine; D000071063:Endoglin; D005260:Female; D005865:Gestational Age; D006400:Hematocrit; D047908:Intracellular Signaling Peptides and Proteins / Q000097:blood; D023421:Models, Animal; D000072483:Placenta Growth Factor; D011225:Pre-Eclampsia / Q000097:blood* / Q000209:etiology; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000097:blood; D011507:Proteinuria; D051381:Rats; D017207:Rats, Sprague-Dawley; D016212:Transforming Growth Factor beta / Q000097:blood; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood
D042501:Angiogenic Proteins; D002018:Bufanolides; D000071063:Endoglin; C501740:Eng protein, rat; D047908:Intracellular Signaling Peptides and Proteins; C000608038:Pgf protein, rat; D011257:Pregnancy Proteins; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D000072483:Placenta Growth Factor; C005734:bufogenin; C093896:marinobufagenin; D003404:Creatinine; C501164:Flt1 protein, rat; D040281:Vascular Endothelial Growth Factor Receptor-1