title: Antihypertensive drugs methyldopa, labetalol, hydralazine, and clonidine improve trophoblast interaction with endothelial cellular networks in vitro.
abstract: OBJECTIVE
  The interaction between trophoblasts and maternal endothelium is important for placental vascular modeling. Failure of uterine spiral artery transformation is linked to the etiopathology of preeclampsia. Antihypertensive medications used to control hypertension in early pregnancy can alter placental and circulating cytokines. This study investigated whether selected antihypertensive drugs can modulate the interaction between trophoblast and endothelial cells.
  
  
  METHODS
  Human uterine myometrial microvascular endothelial cells were preincubated with (or without) low-dose tumor necrosis factor-α (TNF-α; 0.5 ng/ml) or TNF-α and soluble fms-like tyrosine kinase 1 (sFlt-1; 100 ng/ml). Red fluorescent-labeled endothelial cells were then cultured on Matrigel. After appearance of endothelial cellular networks, green fluorescent-labeled HTR-8/SVneo trophoblast cells were cocultured in the presence of pharmacological doses of methyldopa, labetalol, hydralazine, and clonidine. Images were captured after 24 h and drug effects on HTR-8/SVneo cell integration were quantified by Image Analysis software. The conditioned medium was collected to measure sFlt-1, vascular endothelial growth factor (VEGF), placental growth factor, interleukin-10, and interleukin-6 by ELISA.
  
  
  RESULTS
  Methyldopa, labetalol, hydralazine, and clonidine increased trophoblast integration into TNF-α-preincubated endothelial cellular networks. In conditioned medium, sFlt-1 was reduced by methyldopa, hydralazine, and clonidine alone. VEGF was increased by methyldopa. A decrease in placental growth factor was seen by methyldopa and also in nontreated endothelial cell coculture of the other three drugs.
  
  
  CONCLUSIONS
  Some antihypertensive drugs used in pregnancy may improve the cellular interaction between trophoblast and endothelial cells exposed to TNF-α. Methyldopa, hydralazine, and clonidine reduced sFlt-1 concentration in culture medium, whereas labetalol increased trophoblast integration independently of sFlt-1. Methyldopa increased VEGF concentration. Some pregnancy-related antihypertensives may affect placental vascularization.
authors.affiliation: aSchool of Medicine, University of Western Sydney, Penrith bRenal Unit, Liverpool Hospital, Liverpool cVascular Immunology Research Laboratory, The Heart Research Institute, University of Sydney, Newtown, New South Wales, Australia.
authors.forename: Bei
authors.initials: B
authors.lastname: Xu
authors.forename: Francesca
authors.initials: F
authors.lastname: Charlton
authors.forename: Angela
authors.initials: A
authors.lastname: Makris
authors.forename: Annemarie
authors.initials: A
authors.lastname: Hennessy
mesh_terms: D000959:Antihypertensive Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003000:Clonidine / Q000494:pharmacology; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D005260:Female; D006801:Humans; D006830:Hydralazine / Q000494:pharmacology; D066298:In Vitro Techniques; D007741:Labetalol / Q000494:pharmacology; D008750:Methyldopa / Q000494:pharmacology; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects*
chemical_list: D000959:Antihypertensive Agents; D017077:Culture Media, Conditioned; D016207:Cytokines; D006830:Hydralazine; D008750:Methyldopa; D003000:Clonidine; D007741:Labetalol