title: Hypertension in response to placental ischemia during pregnancy: role of B lymphocytes.
abstract: Preeclampsia is associated with innate inflammatory response resulting in elevated tumor necrosis factor-α, agonistic autoantibodies to the angiotensin II type I receptor, and activation of endothelin 1 (ET-1). This study was designed to determine the role of B-cell depletion, resulting in agonistic autoantibodies to the angiotensin II type I receptor suppression to mediate hypertension via activation of ET-1 in the placental ischemic reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. To achieve this goal we examined the effect of RUPP on mean arterial pressure and ET-1 in the presence and absence of chronically infused rituximab (R; 250 mg/kg), a B-lymphocyte-suppressive agent used clinically to treat autoimmune diseases. Mean arterial pressure was 103±1 mm Hg in normal pregnant (NP) rats; 103±3 mm Hg in NP+R versus 133±2 mm Hg in RUPP rats, and 118±2 mm Hg in RUPP+R rats (P<0.001 vs RUPP controls). B lymphocytes decreased from 6.0±0.5% gated cells in RUPP to 3.7±0.8% gated cells in RUPP+R rats. Importantly, agonistic autoantibodies to the angiotensin II type I receptor decreased from 18±1 bpm in RUPP rats to 10±1 bpm in RUPP+R rats. ET-1 decreased 1.5-fold in kidneys and 4-fold in the placenta (P<0.01) of RUPP+R versus RUPP rats. Media ET-1 excretion from endothelial cells exposed to serum from NP, RUPP, NP+R, or RUPP+R rats was determined. ET-1 from endothelial cells treated with NP serum was 53+13 pg/mg and increased to 75+10 pg/mg with RUPP serum. In contrast, ET-1 secretion decreased in response to B-cell-depleted RUPP serum to 50±8 pg/mg and was unchanged in response to NP+R sera (46±12 pg/mg). These data demonstrate the important roles that B-lymphocyte activation and agonistic autoantibodies to the angiotensin II type I receptors play in the pathophysiology of hypertension in response to placental ischemia.
authors.affiliation: Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 39216-4505, USA. bblamarca@physiology.umsmed.edu
authors.forename: Babbette
authors.initials: B
authors.lastname: LaMarca
authors.forename: Kedra
authors.initials: K
authors.lastname: Wallace
authors.forename: Florian
authors.initials: F
authors.lastname: Herse
authors.forename: Gerd
authors.initials: G
authors.lastname: Wallukat
authors.forename: James N
authors.initials: JN
authors.lastname: Martin
authors.forename: Abram
authors.initials: A
authors.lastname: Weimer
authors.forename: Ralf
authors.initials: R
authors.lastname: Dechend
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D001794:Blood Pressure / Q000276:immunology; D002478:Cells, Cultured; D004461:Eclampsia / Q000209:etiology / Q000276:immunology* / Q000503:physiopathology; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology; D019332:Endothelin-1 / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007511:Ischemia / Q000150:complications* / Q000276:immunology / Q000503:physiopathology; D010920:Placenta / Q000098:blood supply* / Q000276:immunology / Q000503:physiopathology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000069283:Rituximab; D014599:Uterus / Q000276:immunology / Q000503:physiopathology
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D001323:Autoantibodies; D019332:Endothelin-1; D044140:Receptor, Angiotensin, Type 1; D000069283:Rituximab