Negative regulation of soluble Flt-1 and soluble endoglin release by heme oxygenase-1.
BACKGROUND
Preeclampsia is characterized clinically by hypertension and proteinuria. Soluble Flt-1 (sFlt-1; also known as soluble vascular endothelial growth factor receptor-1 [VEGFR-1]) and soluble endoglin (sEng) are elevated in preeclampsia, and their administration to pregnant rats elicits preeclampsia-like symptoms. Heme oxygenase-1 (HO-1) and its metabolite carbon monoxide (CO) exert protective effects against oxidative stimuli. Thus, we hypothesized that HO-1 upregulation may offer protection against preeclampsia by inhibiting sFlt-1 and sEng release.


RESULTS
Preeclamptic villous explants secreted high levels of sFlt-1 and sEng. Adenoviral overexpression of HO-1 in endothelial cells inhibited VEGF-mediated sFlt-1 release and interferon-gamma- and tumor necrosis factor-alpha-induced sEng release, whereas HO-1 inhibition potentiated sFlt-1 and sEng production from endothelial cells and placental villous explants. Consistent with these findings, mice lacking HO-1 produced higher levels of sFlt-1 and sEng compared with wild-type mice. Using selective ligands (VEGF-E and placental growth factor) and a receptor-specific inhibitor (SU-1498), we demonstrated that VEGF-induced sFlt-1 release was VEGFR-2 dependent. Furthermore, CO-releasing molecule-2 (CORM-2) or CO decreased sFlt-1 release and inhibited VEGFR-2 phosphorylation. Treatment of endothelial cells with statins upregulated HO-1 and inhibited the release of sFlt-1, whereas vitamins C and E had no effect.


CONCLUSIONS
The present study demonstrates that the HO-1/CO pathway inhibits sFlt-1 and sEng release, providing compelling evidence for a protective role of HO-1 in pregnancy, and identifies HO-1 as a novel target for the treatment of preeclampsia.
Cudmore
Melissa
M
Department of Reproductive and Vascular Biology, Medical School, University of Birmingham, Edgbaston, Birmingham, West Midlands, B15 2TT, UK.
Ahmad
Shakil
S
Al-Ani
Bahjat
B
Fujisawa
Takeshi
T
Coxall
Heather
H
Chudasama
Kunal
K
Devey
Luke R
LR
Wigmore
Stephen J
SJ
Abbas
Allyah
A
Hewett
Peter W
PW
Ahmed
Asif
A
D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D000975:Antioxidants / Q000494:pharmacology; D002248:Carbon Monoxide / Q000494:pharmacology; D015687:Cell Hypoxia; D002478:Cells, Cultured / Q000187:drug effects; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D000071063:Endoglin; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D005822:Genetic Vectors; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000502:physiology*; D051547:Heme Oxygenase-1 / Q000172:deficiency / Q000502:physiology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D009942:Organometallic Compounds / Q000494:pharmacology; D018384:Oxidative Stress; D010920:Placenta / Q000473:pathology; D000072483:Placenta Growth Factor; D011225:Pre-Eclampsia / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D011956:Receptors, Cell Surface / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012995:Solubility; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology
D015703:Antigens, CD; D000975:Antioxidants; D016895:Culture Media, Serum-Free; C064206:ENG protein, human; D000071063:Endoglin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009942:Organometallic Compounds; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; C000608038:Pgf protein, rat; D011257:Pregnancy Proteins; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C447082:tricarbonyldichlororuthenium (II) dimer; D000072483:Placenta Growth Factor; D002248:Carbon Monoxide; D007371:Interferon-gamma; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C491523:Hmox1 protein, rat; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2