title: Blockade of CD40 ligand for intercellular communication reduces hypertension, placental oxidative stress, and AT1-AA in response to adoptive transfer of CD4+ T lymphocytes from RUPP rats.
abstract: Preeclampsia (PE) is associated with altered immune activation during pregnancy. We have previously shown that adoptive transfer of CD4(+) T cells from the reduced uterine perfusion pressure (RUPP) rat model of PE increases blood pressure, oxidative stress (ROS), and inflammation in normal pregnant recipient rats. The objective of this study was to determine if blockade of communication via the CD40-CD40 ligand (CD40L) interaction between placental ischemia-induced CD4(+) T cells with endogenous normal pregnant (NP) cells would improve pathophysiology that was previously observed in NP recipient rats of RUPP CD4(+) T cells. Splenic CD4(+) T lymphocytes were magnetically separated, incubated with 2.5 μg/ml anti-CD40 ligand (αCD40L) overnight, and transferred into NP rats on day 12 of gestation (NP+RUPP CD4(+) T+anti-CD40L). On day 19 of gestation, blood pressure (MAP), blood, and tissues were collected. MAP was 99 ± 2 in NP (n = 13), 116 ± 4 in NP+RUPP CD4(+) T cells (n = 7; P < 0.01); MAP only increased to 104 ± 2 in NP+RUPP CD4(+) T cells+CD40L (n = 24) (P < 0.05 vs. NP+RUPP CD4(+) T cells). Mechanisms of hypertension in response to RUPP CD4(+) T cells include endothelin-1 (ET-1), ROS, and angiotensin II type I receptor (AT1-AA) were analyzed. Inhibition of CD40L binding reduced placental ET-1 to 2.3-fold above NP rats and normalized placental ROS from 318.6 ± 89 in NP+RUPP CD4(+) T cells (P < 0.05) to 118.7 ± 24 in NP+RUPP CD4(+) T+anti-CD40L (P < 0.05). AT1-AA was also normalized with inhibition of CD40L. These data suggest that placental ischemia-induced T-cell communication via the CD40L is one important mechanism leading to much of the pathophysiology of PE.
authors: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi;
authors: Denise C
authors: DC
authors: Cornelius
authors: Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, Mississippi;
authors: Javier
authors: J
authors: Castillo
authors: Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, Mississippi;
authors: Justin
authors: J
authors: Porter
authors: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi;
authors: Lorena M
authors: LM
authors: Amaral
authors: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi;
authors: Nathan
authors: N
authors: Campbell
authors: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi;
authors: Adrienne
authors: A
authors: Paige
authors: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi;
authors: Alexia J
authors: AJ
authors: Thomas
authors: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi;
authors: Ashlyn
authors: A
authors: Harmon
authors: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi;
authors: Mark W
authors: MW
authors: Cunningham
authors: Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, Mississippi;
authors: Kedra
authors: K
authors: Wallace
authors: Experimental and Clinical Research Center, Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany; and.
authors: Florian
authors: F
authors: Herse
authors: Experimental and Clinical Research Center, Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany; and.
authors: Gerd
authors: G
authors: Wallukat
authors: Experimental and Clinical Research Center, Max-Delbrück Center for Molecular Medicine in the Helmholtz Association and the Charité Medical Faculty, Berlin, Germany; and HELIOS-Klinikum, Berlin, Germany.
authors: Ralf
authors: R
authors: Dechend
authors: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi; Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, Mississippi; bblamarca@umc.edu.
authors: Babbette
authors: B
authors: LaMarca
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology / Q000637:transplantation*; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism*; D002450:Cell Communication / Q000502:physiology*; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006973:Hypertension / Q000378:metabolism; D007511:Ischemia / Q000503:physiopathology; D018384:Oxidative Stress; D010920:Placenta / Q000502:physiology*; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D014599:Uterus / Q000098:blood supply
chemical_list: D019013:CD40 Antigens; D019332:Endothelin-1; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1
keywords: B cells; T cells; hypertension; preeclampsia