title: Induction of heme oxygenase-1 attenuates sFlt-1-induced hypertension in pregnant rats.
abstract: Preeclampsia (PE) is one of the leading causes of fetal and maternal morbidity, affecting 5-10% of all pregnancies, and lacks an effective treatment. The exact etiology of the disorder is unclear, but placental ischemia has been shown to be a central causative agent. In response to placental ischemia, the antiangiogenic protein fms-like tyrosine kinase-1 (sFlt-1), a VEGF antagonist, and reactive oxygen species are secreted, leading to the maternal syndrome. One promising therapeutic approach to treat PE is through manipulation of the heme oxygenase-1 (HO-1) protein. It has been previously reported that HO-1 and carbon monoxide downregulate sFlt-1 production in vitro, and we have recently shown that HO-1 induction significantly attenuates placental ischemia-induced hypertension, partially through normalization of the sFlt-1-to-VEGF ratio in the placenta. The purpose of this study was to determine whether HO-1 induction would have beneficial effects independently of sFlt-1 suppression. To that end, pregnant rats were continuously infused with recombinant sFlt-1 from gestational days 14-19, and circulating sFlt-1 increased approximately twofold, similar to rats with experimentally induced placental ischemia. In response, mean arterial pressure increased 17 mmHg, which was completely normalized by HO-1 induction. Unbound circulating VEGF was decreased ∼17% in response to sFlt-1 infusion but was increased ∼50% in response to HO-1 induction. Finally, endothelial function was improved as measured by reductions in vascular expression of preproendothelin mRNA. In conclusion, manipulation of HO-1 presents an intriguing therapeutic approach to the treatment of PE.
authors.affiliation: Department of Physiology and Biophysics and Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: George
authors.forename: Marietta
authors.initials: M
authors.lastname: Arany
authors.forename: Kathy
authors.initials: K
authors.lastname: Cockrell
authors.forename: Megan V
authors.initials: MV
authors.lastname: Storm
authors.forename: David E
authors.initials: DE
authors.lastname: Stec
authors.forename: Joey P
authors.initials: JP
authors.lastname: Granger
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D001794:Blood Pressure / Q000187:drug effects*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D019332:Endothelin-1 / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology; D004790:Enzyme Induction; D005260:Female; D005865:Gestational Age; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D010920:Placenta / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D011225:Pre-Eclampsia / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D011247:Pregnancy; D011524:Protoporphyrins / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D040281:Vascular Endothelial Growth Factor Receptor-1
chemical_list: D000959:Antihypertensive Agents; D019332:Endothelin-1; D011524:Protoporphyrins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; C007095:cobaltiprotoporphyrin; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D040281:Vascular Endothelial Growth Factor Receptor-1