Effects of anti-hypertensive drugs on production of soluble fms-like tyrosine kinase 1 and soluble endoglin from human normal and pre-eclamptic placentas in vitro.
1. Increases in soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng) contribute to the pathogenesis of pre-eclampsia. Soluble Flt-1 binds to circulating free vascular endothelial growth factor and placenta growth factor and this is associated with endothelial dysfunction. Soluble endoglin, a transforming growth factor (TGF)-beta coreceptor, was reported to synergize with sFlt-1 to amplify endothelial dysfunction by inhibiting TGF-beta1-mediated vasorelaxation. 2. The aim of the present study was to examine whether the antihypertensive drugs clonidine (0.08-1.3 microg/mL), diazoxide (25-300 microg/mL), frusemide (60-1000 microg/mL) and hydralazine (6.3-100 microg/mL) have any effect on placental production of sFlt-1 and sEng in placentas from normal and pre-eclamptic pregnancies. 3. Explants were taken from non-laboured term placentas of normal pregnancy (n = 5) and women with pre-eclampsia (n = 5). Villous explants were cultured with increasing doses of antihypertensive drugs. Placental sFlt-1 and sEng production was examined using ELISA. 4. Baseline sFlt-1 production was higher in placentas from women with pre-eclampsia than from normal pregnancy (4.5 +/- 1.4 vs 3.2 +/- 0.6 ng/mg of total protein, respectively; P < 0.001), as was sEng production (9.0 +/- 2.3 vs 4.1 +/- 0.6 ng/mg of total protein, respectively; P < 0.001). With the exception of frusemide, none of the antihypertensive drugs tested had any effect on sFlt-1 and sEng production from placental explants of normal pregnancy and women with pre-eclampsia. Increasing frusemide concentrations were correlated with increased sEng production in normal pregnancy (P < 0.005). 5. In conclusion, placental sFlt-1 and sEng production was higher in pre-eclampsia and antihypertensive drugs had no effect on placental production of sFlt-1 and sEng in vitro.
Xu
B
B
Vascular Immunology Research Laboratory, The Heart Research Institute, University of Sydney, 114 Pyrmont Bridge Road, Camperdown, NSW 2050, Australia. bei_xu2001@yahoo.com
Thornton
C
C
Tooher
J
J
Ogle
R
R
Lim
S
S
Makris
A
A
Hennessy
A
A
D000328:Adult; D015703:Antigens, CD / Q000096:biosynthesis*; D000959:Antihypertensive Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000071063:Endoglin; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005865:Gestational Age; D006801:Humans; D066298:In Vitro Techniques; D010920:Placenta / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011225:Pre-Eclampsia / Q000201:enzymology / Q000378:metabolism*; D011247:Pregnancy; D011956:Receptors, Cell Surface / Q000096:biosynthesis*; D012995:Solubility; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis*
D015703:Antigens, CD; D000959:Antihypertensive Agents; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1