Human trophoblast-derived hydrogen sulfide stimulates placental artery endothelial cell angiogenesis

• Published in: Biology of reproduction 2017-09, Vol.97 (3), p.478-489
• Main Authors: Chen, Dong-Bao, Feng, Lin, Hodges, Jennifer K, Lechuga, Thomas J, Zhang, Honghai
• Format: Article
• Language: English
• Subjects: AKT protein; AKT1 protein; Angiogenesis; Angiogenesis Inducing Agents - pharmacology; Animals; Arteries - cytology; Arteries - drug effects; Cell culture; Cell Differentiation - drug effects; Cell Line; Cell lines; Cell migration; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Coculture Techniques; Cystathionine b-synthase; Cystathionine beta-Synthase - antagonists & inhibitors; Cystathionine beta-Synthase - biosynthesis; Cystathionine g-lyase; Cystathionine gamma-Lyase - antagonists & inhibitors; Cystathionine gamma-Lyase - biosynthesis; Endothelial cells; Endothelial Cells - drug effects; Female; human; Humans; Hydrogen sulfide; Hydrogen Sulfide - pharmacology; Kinases; L-Alanine; MAP kinase; MAP Kinase Signaling System - drug effects; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; Nitric oxide; Nitric Oxide Synthase Type III - antagonists & inhibitors; Nitric Oxide Synthase Type III - metabolism; Nitric-oxide synthase; Placenta; Placenta - blood supply; PREGNANCY; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Sheep; Thymoma; Trophoblasts; Trophoblasts - chemistry; Vascular endothelial growth factor
• ISSN: 0006-3363; 1529-7268
• DOI: 10.1093/biolre/iox105

Endogenous hydrogen sulfide (H2S), mainly synthesized by cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH), has been implicated in regulating placental angiogenesis; however, the underlying mechanisms are unknown. This study was to test a hypothesis that trophoblasts synthesize H2S to promote placental angiogenesis. Human choriocarcinoma-derived BeWo cells expressed both CBS and CTH proteins, while the first trimester villous trophoblast-originated HTR-8/SVneo cells expressed CTH protein only. The H2S producing ability of BeWo cellswas significantly inhibited by either inhibitors of CBS (carboxymethyl hydroxylamine hemihydrochloride, CHH) or CTH (β-cyano-L-alanine, BCA) and that in HTR-8/SVneo cells was inhibited by CHH only. H2S donors stimulated cell proliferation, migration, and tube formation in ovine placental artery endothelial cells (oFPAECs) as effectively as vascular endothelial growth factor. Co-culture with BeWo and HTR-8/SVneo cells stimulated oFPAEC migration, which was inhibited by CHH or BCA in BeWo but CHH only in HTR-8/SVneo cells. Primary human villous trophoblasts (HVT) were more potent than trophoblast cell lines in stimulating oFPAEC migration that was inhibited by CHH and CHH/BCA combination in accordance with its H2S synthesizing activity linked to CBS and CTH expression patterns. H2S donors activated endothelial nitric oxide synthase (NOS3), v-AKT murine thymoma viral oncogene homolog 1 (AKT1), and extracellular signal-activated kinase 1/2 (mitogen-activated protein kinase 3/1, MAPK3/1) in oFPAECs. H2S donor-induced NOS3 activation was blocked by AKT1 but not MAPK3/1 inhibition. In keeping with our previous studies showing a crucial role of AKT1,MAPK3/1, and NOS3/NO in placental angiogenesis, these data show that trophoblast-derived endogenous H2S stimulates placental angiogenesis, involving activation of AKT1, NOS3/NO, and MAPK3/1. Summary Sentence Human trophoblast-derived endogenous H2S mediates trophoblast-endothelial cell interaction in stimulating placental artery endothelial cell angiogenesis in vitro.