Hypoxia downregulates the angiogenesis in human placenta via Notch1 signaling pathway

Abstract

Placentation, which is critical for maternal-fetal exchange of nutrients and gases, is a complicated process comprising stepwise vasculogenesis and angiogenesis. Hypoxia caused by impaired trophoblast invasion may cause various angiogenic abnormalities in human placenta. The Notch1 signaling pathway plays an important role in the regulation of angiogenesis. The angiogenesis of human umbilical vein endothelial cells (HUVECs) under normal/hypoxic conditions and the mRNA/protein level of Notch1/Dell4/Jagged1 were investigated in this study. The effects of DAPT/JAG-1 on the migration of HUVECs were also assessed by cell wound healing assay, so as to discover the possible role of notch1 signaling pathway in the angiogenesis of human placenta. The results showed that angiogenic ability of HUVECs was seriously reduced under hypoxic conditions. The mRNA and protein levels of Notch1/Dell4/Jagged1 were decreased in the hypoxic group compared to the control one. In addition, the migration capability of HUVECs was significantly obstructed when treated with DAPT and under hopoxic condition, but promoted when treated with JAG-1. The above results demonstrate that hypoxia downregulates the angiogenesis in human placenta via Notch1 signaling pathway.

Keywords

hypoxia / Notch1 / Dell4 / Jagged1 / angiogenesis / human umbilical vein endothelial cells / placenta

References

[1] DemirR, KayisliUA, CayliS, et al. . Sequential steps during vasculogenesis and angiogenesis in the very early human placenta. Placenta, 2006, 27(6-7): 535-539 PMID: 16029887

[2] SwiatekPJ, LindsellCE, del AmoFF, et al. . Notch1 is essential for postimplantation development in mice. Genes Dev, 1994, 8: 707-719 PMID: 7926761

[3] HofmannJJ, Luisa Iruela-ArispeM. Notch expression patterns in the retina: An eye on receptor-ligand distribution during angiogenesis. Gene Expr Patterns, 2007, 7(4): 461-470 PMID: 17161657

[4] HellströmM, PhngLK, HofmannJJ, et al. . Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature, 2007, 445(7129): 776-780 PMID: 17259973

[5] NucciMR, CastrillonDH, BaiH, et al. . Biomarkers in diagnostic obstetric and gynecologic pathology: a review. Adv Anat Pathol, 2003, 10(2): 55-68 PMID: 12605088

[6] ShutterJR, ScullyS, FanW, et al. . Delta4, a novel Notch ligand expressed in arterial endothelium. Genes Dev, 2000, 14(11): 1313-1318 PMID: 10837024 PMCID: 316657

[7] BeneditoR, DuarteA. Expression of Dll4 during mouse embryogenesis suggests multiple developmental roles. Gene Expr Patterns, 2005, 5(6): 750-755 PMID: 15923152

[8] ClaxtonS M. Fruttiger. Periodic Delta-like 4 expression in developing retinal arteries. Gene Expr Patterns, 2004, 5(1): 123-127 PMID: 15533827

[9] MailhosC, ModlichU, LewisJ, et al. . Delta4, an endothelial specific Notch ligand expressed at sites of physiological and tumor angiogenesis. Differentiation, 2001, 69(2-3): 135-144 PMID: 11798067

[10] KakiganoA, TomimatsuT, MimuraK, et al. . Drug repositioning for preeclampsia therapeutics by in vitro screening: Phosphodiesterase-5 inhibitor vardenafil restores endothelial dysfunction via induction of placental growth factor. Reprod Sci, 2015, 22(10): 1272-1280 PMID: 25736325

[11] TangM, YangY, YuJ, et al. . Discordant mRNA and protein expression of CXCR4 under in vitro CoCl2-induced hypoxic conditions. Biochem Biophys Res Commun, 2017, 484(2): 285-291 PMID: 28126341

[12] ZhangY, XuY, MaJ, et al. . Adrenomedullin promotes angiogenesis in epithelial ovarian cancer through upregulating hypoxia-inducible factor-1a and vascular endothelial growth factor. Sci Rep, 2017, 7: 40524 PMID: 28091613 PMCID: 5238385

[13] TanY, XieZ, DingM, et al. . Increased levels of FoxA1 transcription factor in pluripotent P19 embryonal carcinoma cells stimulate neural differentiation. Stem Cells Dev, 2010, 19(9): 1365-1374 PMID: 19916800

[14] XieZ, TanG, DingM, et al. . Foxm1 transcription factor is required for maintenance of pluripotency of P19 embryonal carcinoma cells. Nucleic Acids Res, 2010, 38(22): 8027-8038 PMID: 20702419 PMCID: 3001083

[15] KalkaC, AsaharaT, KroneW, et al. . Angiogenesis and vasculogenesis. Therapeutic strategies for stimulation of postnatal neovascularization. Herz, 2000, 25(6): 611-622 PMID: 11076319

[16] HarapanH, AndalasM, MudhakirD, et al. . Micro RNA: New aspect in pathobiology of preeclampsia?. Egypt J Med Hum Genet, 2012, 13: 127-131

[17] CarlesD, PelluardF, AndréG, et al. . Placental pathology of uteroplacental vascular deficiency. Ann Pathol, 2013, 33(4): 230-236 PMID: 23954115

[18] MandòC, De PalmaC, StampalijaT, et al. . Placental mitochondrial content and function in intrauterine growth restriction and preeclampsia. Am J Physiol Endocrinol Metab, 2014, 306(4): 404

[19] FiguerasF, GratacosE. Stage-based approach to the management of fetal growth restriction. Prenat Diagn, 2014, 34(7): 655-659 PMID: 24839087

[20] GirardiG, YarilinD, ThurmanJM, et al. . Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction. J Exp Med, 2006, 203(9): 2165-2175 PMID: 16923853 PMCID: 2118387

[21] GasperowiczM, OttoF. The Notch signalling pathway in the development of the mouse Placenta. placenta, 2008, 29(8): 651-659 PMID: 18603295

[22] KrebsLT, XueY, NortonCR, et al. . Notch signaling is essential for vascular morphogenesis in mice. Genes Dev, 2000, 14(11): 1343-1352 PMID: 10837027 PMCID: 316662

[23] GaleNW, DominguezMG, NogueraI, et al. . Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. Proc Natl Acad Sci USA, 2004, 101(45): 15949-15954 PMID: 15520367 PMCID: 524697

[24] Duarte A, Hirashima M, Benedito R, et al. Dosage-sensitive requirement for mouse Dll4 in artery development. Genes Dev 2004,18(20):2474–2478

[25] KrebsLT, ShutterJR, TanigakiK, et al. . Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants. Genes Dev, 2004, 18(20): 2469-2473 PMID: 15466160 PMCID: 529533

[26] HerrF, SchreinerI, BaalN, et al. . Expression patterns of Notch receptors and their ligands Jagged and Delta in human placenta. Placenta, 2011, 32: 554-563 PMID: 21726900

[27] CobellisL, MastrogiacomoA, FedericoE, et al. . Distribution of Notch protein members in normal and preeclampsia-complicated placentas. Cell Tissue Res, 2007, 330(3): 527-534 PMID: 17955263

[28] SahinZ, AcarN, OzbeyO, et al. . Distribution of Notch family proteins in intrauterine growth restriction and hypertension complicated human term placentas. Acta Histochemica, 2011, 113(3): 270-276 PMID: 19913284

[29] ZhaoWX, HuangTT, JiangM, et al. . Expression of notch family proteins in placentas from patients with early-onset severe preeclampsia. Reprod Sci, 2014, 21(6): 716-723 PMID: 24336671 PMCID: 4016722

[30] CaiHR, LiuHY, QiaoFY, et al. . Effect of hypoxia on endothelial cells injury of human umbilical vein and expression of soluble vascular endothelial growth factor receptor-1 mRNA. Zhongguo Fuyou Baojian Zazhi (Chinese), 2009, 11(24): 1559-1661

[31] De FalcoM, CobellisL, GiraldiD, et al. . Expression and distribution of notch protein members in human placenta throughout pregnancy. Placenta, 2007, 28(2-3): 118-126 PMID: 17185135

[32] DoveyHF, JohnV, AndersonJP, et al. . Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J Neurochem, 2001, 76: 173181

[33] SearfossGH, JordanWH, CalligaroDO, et al. . Adipsin, a biomarker of gastrointestinal toxicity mediated by a functional secretase inhibitor. J Biol Chem, 2003, 278: 46107-46116 PMID: 12949072

[34] MunnamalaiV, HayashiT, Bermingham-McDonoghO. Notch prosensory effects in the mammalian cochlea are partially mediated by Fgf20. J Neurosci, 2012, 32(37): 12876-12884 PMID: 22973011 PMCID: 3525448

[35] ZhouJX, HanJB, ChenSM, et al. . secretase inhibition combined with cisplatin enhances apoptosis of nasopharyngeal carcinoma cells. Exp Ther Med, 2012, 3(2): 357-361 PMID: 22969896

[36] YuanYY, ZengZY, ChenJM. Effect of DAPT on proliferation and apoptosis of human multiple myeloma cell line RPMI8226. Zhongguo Shi Yan Xue Ye Xue Za Zhi (Chinese), 2012, 20(4): 922-925

[37] NikueiP, MalekzadehK, RajaeiM, et al. . The imbalance in expression of angiogenic and anti-angiogenic factors as candidate predictive biomarker in preeclampsia. Iran J Reprod Med, 2015, 13(5): 251-262 PMID: 26221124 PMCID: 4515231

[38] ChenY, ZhangY, DengQ, et al. . Inhibition of Wnt inhibitory factor 1 under hypoxic condition in human umbilical vein endothelial cells promoted angiogenesis in vitro. Reprod Sci, 2016, 23(10): 1348-1358 PMID: 26994065

[39] LiaoWX, WingDA, GengJG, et al. . Perspectives of SLIT/ROBO signaling in placental angiogenesis. Histol Histopathol, 2010, 25(9): 1181-1190 PMID: 20607660