Angiotensin II and angiotensin-(1-7) decrease sFlt1 release in normal but not preeclamptic chorionic villi: an in vitro study.
BACKGROUND
During preeclampsia, placental angiogenesis is impaired. Factors released from the placenta including vascular endothelial growth factor (VEGF), placental growth factor (PLGF), soluble VEGF receptor 1 (sFlt1), and soluble endoglin (sEng) are regulatory molecules of placental development and function. While the renin angiotensin system has been shown to regulate angiogenic factors in other research fields, these mechanisms have not been extensively studied during pregnancy.


METHODS
We evaluated the effects of angiotensin II (Ang II) and angiotensin-(1-7) [Ang-(1-7)] on the release of VEGF, PLGF, sFlt1, and sEng from placental chorionic villi (CV). CV were collected from nulliparous third-trimester normotensive and preeclamptic subjects. CV were incubated for 0, 2, 4, and 16 hours with or without Ang II (1 nM and 1 microM) or Ang-(1-7) (1 nM and 1 microM). The release of VEGF, PLGF, sFlt1, sEng, lactate dehydrogenase (LDH), and human placenta lactogen (HPL) was measured by ELISA.


RESULTS
The release of sFlt1, PLGF, sEng from normal and preeclamptic CV increased over time. Release of sFlt1 and sEng was significantly higher from preeclamptic CV. VEGF was below the detectable level of the assay in normal and preeclamptic CV. After 2 hours, sFlt1 release from normal CV was significantly inhibited with Ang II (1 nM and 1 microM) and Ang-(1-7) (1 nM and 1 microM). There was a time-dependent increase in HPL indicating that the CV were functioning normally.


CONCLUSIONS
Our study demonstrates a critical inhibitory role of angiotensin peptides on sFlt1 in normal pregnancy. Loss of this regulation in preeclampsia may allow sFlt1 to increase resulting in anti-angiogenesis and end organ damage in the mother.
Hypertension and Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Lauren
L
Anton
David C
DC
Merrill
Liomar A A
LA
Neves
Courtney
C
Gruver
Cheryl
C
Moorefield
K Bridget
KB
Brosnihan
D000328:Adult; D000803:Angiotensin I / Q000494:pharmacology*; D000804:Angiotensin II / Q000494:pharmacology*; D000809:Angiotensins / Q000378:metabolism; D002478:Cells, Cultured; D002824:Chorionic Villi / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D008875:Middle Aged; D010446:Peptide Fragments / Q000494:pharmacology*; D010920:Placenta / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D021041:Placental Circulation / Q000187:drug effects / Q000502:physiology; D010928:Placental Lactogen / Q000378:metabolism; D011225:Pre-Eclampsia / Q000378:metabolism / Q000473:pathology*; D011247:Pregnancy; D020033:Protein Isoforms / Q000378:metabolism; D012995:Solubility; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000737:chemistry / Q000378:metabolism*; D055815:Young Adult
D000809:Angiotensins; D010446:Peptide Fragments; D020033:Protein Isoforms; D042461:Vascular Endothelial Growth Factor A; D000804:Angiotensin II; D010928:Placental Lactogen; D000803:Angiotensin I; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; C118790:angiotensin I (1-7)