Peroxisome proliferator‑activated receptor γ mediates porcine placental angiogenesis through hypoxia inducible factor‑, vascular endothelial growth factor‑ and angiopoietin‑mediated signaling

Zhang,Juzuo; Peng,Xuan; Yuan,Anwen; Xie,Yang; Yang,Qing; Xue,Liqun

doi:10.3892/mmr.2017.6903

Peroxisome proliferator‑activated receptor γ mediates porcine placental angiogenesis through hypoxia inducible factor‑, vascular endothelial growth factor‑ and angiopoietin‑mediated signaling

Authors:
- Juzuo Zhang
- Xuan Peng
- Anwen Yuan
- Yang Xie
- Qing Yang
- Liqun Xue
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Affiliations: Department of Clinic Veterinary Medicine, College of Veterinary Medicine, Hunan Agricultural University, Changsha, Hunan 410128, P.R. China
Published online on: June 30, 2017 https://doi.org/10.3892/mmr.2017.6903
Pages: 2636-2644
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Peroxisome proliferator-activated receptor (PPAR) γ has been reported to be implicated in placentation in mice. Previous studies have demonstrated that PPARγ is also expressed in porcine placenta, primarily localized in vascular endothelial cells (VECs). The present study aimed to investigate the roles of PPARγ during porcine placental angiogenesis and examine the molecular mechanisms involved in its actions. VECs were incubated with the PPARγ agonist rosiglitazone and the antagonist T0070907, and their angiogenic potential was evaluated using cellular impedance, wound healing and tube formation assays. Reverse transcription‑quantitative polymerase chain reaction was used to assess the mRNA expression levels of angiogenic factors, including hypoxia‑inducible factors (HIFs), vascular endothelial growth factor (VEGF) isoforms, VEGF receptors (VEGFRs) and angiopoietins (Angs). The results demonstrated that the adhesive, proliferative and migratory capabilities of VECs were potentiated by rosiglitazone and suppressed by T0070907. Notably, tube formation was invariably promoted during PPARγ activation and blockade. The mRNA expression levels of HIF1α, HIF2α, VEGFR2, VEGF188 and Ang‑1 were revealed to be upregulated following treatment of VECs with rosiglitazone, whereas they were downregulated following treatment with T0070907. However, the mRNA expression levels of placental growth factor and VEGF120 were consistently downregulated following PPARγ activation and blockade, whereas VEGF164 mRNA levels remained unaltered. The results of the present study suggested that PPARγ may mediate porcine placental angiogenesis, by interfering with HIF‑, VEGF‑ and angiopoietin‑mediated signaling pathways.

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1	Risau W and Flamme I: Vasculogenesis. Annu Rev Cell Dev Biol. 11:73–91. 1995. View Article : Google Scholar : PubMed/NCBI
2	Risau W: Mechanisms of angiogenesis. Nature. 386:671–674. 1997. View Article : Google Scholar : PubMed/NCBI
3	Sato Y, Poynter G, Huss D, Filla MB, Czirok A, Rongish BJ, Little CD, Fraser SE and Lansford R: Dynamic analysis of vascular morphogenesis using transgenic quail embryos. PLoS One. 5:e126742010. View Article : Google Scholar : PubMed/NCBI
4	Charnock-Jones DS, Clark DE, Licence D, Day K, Wooding FB and Smith SK: Distribution of vascular endothelial growth factor (VEGF) and its binding sites at the maternal-fetal interface during gestation in pigs. Reproduction. 122:753–760. 2001. View Article : Google Scholar : PubMed/NCBI
5	Ventureira MR, Sobarzo CMA, Naito M, Zanuzzi C, Barbeito C and Cebral E: Early placental angiogenesis-vascularization and VEGF/KDR receptor expression during mouse organogenesis after perigestational alcohol consumption. Placenta. 36:4912015. View Article : Google Scholar
6	Saharinen P and Alitalo K: The yin, the yang, and the angiopoietin-1. J Clin Invest. 121:2157–2159. 2011. View Article : Google Scholar : PubMed/NCBI
7	Hwang B, Lee SH, Kim JS, Moon JS, Jeung IC, Lee NG, Park J, Hong HJ, Cho YL, Park YJ, et al: Stimulation of angiogenesis and survival of endothelial cells by human monoclonal Tie2 receptor antibody. Biomaterials. 51:119–128. 2015. View Article : Google Scholar : PubMed/NCBI
8	Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ and Holash J: Vascular-specific growth factors and blood vessel formation. Nature. 407:242–248. 2000. View Article : Google Scholar : PubMed/NCBI
9	Jiang YZ, Li Y, Wang K, Dai CF, Huang SA, Chen DB and Zheng J: Distinct roles of HIF1A in endothelial adaptations to physiological and ambient oxygen. Mol Cell Endocrinol. 391:60–67. 2014. View Article : Google Scholar : PubMed/NCBI
10	Burton GJ, Charnock-Jones D and Jauniaux E: Regulation of vascular growth and function in the human placenta. Reproduction. 138:895–902. 2009. View Article : Google Scholar : PubMed/NCBI
11	Soleymanlou N, Jurisica I, Nevo O, Letta F, Zhang X, Zamudio S, Post M and Caniggia I: Molecular evidence of placental hypoxia in preeclampsia. J Clin Endocrinol Metab. 90:4299–4308. 2005. View Article : Google Scholar : PubMed/NCBI
12	Semenza GL: Hypoxia-inducible factors in physiology and medicine. Cell. 148:399–408. 2012. View Article : Google Scholar : PubMed/NCBI
13	Koch S and Claesson-Welsh L: Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb Perspect Med. 2:a0065022012. View Article : Google Scholar : PubMed/NCBI
14	Vempati P, Popel AS and MacGabhann F: Extracellular regulation of VEGF: Isoforms, proteolysis, and vascular patterning. Cytokine Growth Factor Rev. 25:1–19. 2014. View Article : Google Scholar : PubMed/NCBI
15	Grünewald FS, Prota AE, Giese A and Ballmer-Hofer K: Structure-function analysis of VEGF receptor activation and the role of coreceptors in angiogenic signaling. Biochim Biophys Acta. 1804:567–580. 2010. View Article : Google Scholar : PubMed/NCBI
16	Ng YS, Rohan R, Sunday ME, Demello DE and D'amore PA: Differential expression of VEGF isoforms in mouse during development and in the adult. Dev Dyn. 220:112–121. 2001. View Article : Google Scholar : PubMed/NCBI
17	Nieminen T, Toivanen PI, Rintanen N, Heikuraa T, Jauhiainena S, Airennea KJ, Alitaloc K, Marjomäkib V and Ylä-Herttuala S: The impact of the receptor binding profiles of the vascular endothelial growth factors on their angiogenic features. Biochim Biophys Acta. 1840:454–463. 2014. View Article : Google Scholar : PubMed/NCBI
18	Huang Y, Zhao B, Liu Y and Wang N: Peroxisome proliferator-activated receptor gamma regulates the expression of lipid phosphate phosphohydrolase 1 in human vascular endothelial cells. PPAR Res. 2014:7401212014. View Article : Google Scholar : PubMed/NCBI
19	Kepez A, Oto A and Dagdelen S: Peroxisome proliferator-activated receptor-gamma: Novel therapeutic target linking adiposity, insulin resistance, and atherosclerosis. BioDrugs. 20:121–135. 2006. View Article : Google Scholar : PubMed/NCBI
20	Nadra K, Quignodon L, Sardella C, Joye E, Mucciolo A, Chrast R and Desvergne B: PPARgamma in placental angiogenesis. Endocrinology. 151:4969–4981. 2010. View Article : Google Scholar : PubMed/NCBI
21	Meher A, Sundrani D and Joshi S: Maternal nutrition influences angiogenesis in the placenta through peroxisome proliferator activated receptors: A novel hypothesis. Mol Reprod Dev. 82:726–734. 2015. View Article : Google Scholar : PubMed/NCBI
22	Tache V, Ciric A, Moretto-Zita M, Li Y, Peng J, Maltepe E, Milstone DS and Parast MM: Hypoxia and trophoblast differentiation: A key role for PPARγ. Stem Cells Dev. 22:2815–2824. 2013. View Article : Google Scholar : PubMed/NCBI
23	Hasan AU, Ohmori K, Konishi K, Igarashi J, Hashimoto T, Kamitori K, Yamaguchi F, Tsukamoto I, Uyama T, Ishihara Y, et al: Eicosapentaenoic acid upregulates VEGF-A through both GPR120 and PPARγ mediated pathways in 3T3-L1 adipocytes. Mol Cell Endocrinol. 406:10–18. 2015. View Article : Google Scholar : PubMed/NCBI
24	Cines DB, Pollak ES, Buck CA, Loscalzo J, Zimmerman GA, McEver RP, Pober JS, Wick TM, Konkle BA, Schwartz BS, et al: Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood. 91:3527–3561. 1998.PubMed/NCBI
25	Zhang J, Xu J, Yang Q, Yuan A, Yang L and Xue L: Peroxisome proliferator-activated receptor gamma (PPARγ) expression in pig placenta. Mol Med Rep MMR-8037-156015 in press.
26	Hong HX, Zhang YM, Xu H, Su ZY and Sun P: Immortalization of swine umbilical vein endothelial cells with human telomerase reverse transcriptase. Mol Cells. 24:358–363. 2007.PubMed/NCBI
27	Chrusciel M, Bodek G, Kirtiklis L, Lewczuk B, Hyder CL, Blitek A, Kaczmarek MM, Ziecik AJ and Andronowska A: Immortalization of swine umbilical vein endothelial cells (SUVECs) with the simian virus 40 large-T antigen. Mol Reprod Dev. 78:597–610. 2011. View Article : Google Scholar : PubMed/NCBI
28	Young PW, Buckle DR, Cantello BC, Chapman H, Clapham JC, Coyle PJ, Haigh D, Hindley RM, Holder JC, Kallender H, et al: Identification of high-affinity binding sites for the insulin sensitizer rosiglitazone (BRL-49653) in rodent and human adipocytes using a radioiodinated ligand for peroxisomal proliferator-activated receptor gamma. J Pharmacol Exp Ther. 284:751–759. 1998.PubMed/NCBI
29	Zaytseva YY, Wallis NK, Southard RC and Kilgore MW: The PPARgamma antagonist T0070907 suppresses breast cancer cell proliferation and motility via both PPARgamma-dependent and -independent mechanisms. Anticancer Res. 31:813–823. 2011.PubMed/NCBI
30	Dolkart O, Liron T, Chechik O, Somjen D, Brosh T, Maman and Gabet Y: Statins enhance rotator cuff healing by stimulating the COX2/PGE2/EP4 pathway: An in vivo and in vitro study. Am J Sports Med. 42:2869–2876. 2014. View Article : Google Scholar : PubMed/NCBI
31	Koval OA, Sakaeva GR, Fomin AS, Nushtaeva AA, Semenov DV, Kuligina EV, Gulyaeva LF, Gerasimov AV and Richter VA: Sensitivity of endometrial cancer cells from primary human tumor samples to new potential anticancer peptide lactaptin. J Cancer Res Ther. 11:345–351. 2015. View Article : Google Scholar : PubMed/NCBI
32	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
33	Jonkman JE, Cathcart JA, Xu F, Bartolini ME, Amon JE, Stevens KM and Colarusso P: An introduction to the wound healing assay using live-cell microscopy. Cell Adh Migr. 8:440–451. 2014. View Article : Google Scholar : PubMed/NCBI
34	Kakiuchi-Kiyota S, Vetro JA, Suzuki S, Varney ML, Han HY, Nascimento M, Pennington KL, Arnold LL, Singh RK and Cohen SM: Effects of the PPARgamma agonist troglitazone on endothelial cells in vivo and in vitro: Differences between human and mouse. Toxicol Appl Pharmacol. 237:83–90. 2009. View Article : Google Scholar : PubMed/NCBI
35	Murata T, He S, Hangai M, Ishibashi T, Xi XP, Kim S, Hsueh WA, Ryan SJ, Law RE and Hinton DR: Peroxisome proliferator-activated receptor-gamma ligands inhibit choroidal neovascularization. Invest Ophthalmol Vis Sci. 41:2309–2317. 2000.PubMed/NCBI
36	Park BC, Thapa D, Lee JS, Park SY and Kim JA: Troglitazone inhibits vascular endothelial growth factor-induced angiogenic signaling via suppression of reactive oxygen species production and extracellular signal-regulated kinase phosphorylation in endothelial cells. J Pharmacol Sci. 111:1–12. 2009. View Article : Google Scholar : PubMed/NCBI
37	Kim KY, Ahn JH and Cheon HG: Anti-angiogenic action of PPARγ ligand in human umbilical vein endothelial cells is mediated by PTEN upregulation and VEGFR-2 downregulation. Mol Cell Biochem. 358:375–385. 2011. View Article : Google Scholar : PubMed/NCBI
38	Zhang H, Wei T, Jiang X, Li Z, Cui H, Pan J, Zhuang W, Sun T, Liu Z, Zhang Z and Dong H: PEDF and 34-mer inhibit angiogenesis in the heart by inducing tip cells apoptosis via up-regulating PPAR-γ to increase surface FasL. Apoptosis. 21:60–68. 2016. View Article : Google Scholar : PubMed/NCBI
39	Biscetti F, Gaetani E, Flex A, Aprahamian T, Hopkins T, Straface G, Pecorini G, Stigliano E, Smith RC, Angelini F, et al: Selective activation of peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma induces neoangiogenesis through a vascular endothelial growth factor-dependent mechanism. Diabetes. 57:1394–1404. 2008. View Article : Google Scholar : PubMed/NCBI
40	Ndubuizu OI, Tsipis CP, Li A and LaManna JC: Hypoxia-inducible factor-1 (HIF-1)-independent microvascular angiogenesis in the aged rat brain. Brain Res. 1366:101–109. 2010. View Article : Google Scholar : PubMed/NCBI
41	Arreola A, Cowey CL, Coloff JL, Rathmell JC and Rathmell WK: HIF1α and HIF2α exert distinct nutrient preferences in renal cells. PLoS One. 9:e987052014. View Article : Google Scholar : PubMed/NCBI
42	Kaczmarek MM, Kiewisz J, Schams D and Ziecik AJ: Expression of VEGF-receptor system in conceptus during peri-implantation period and endometrial and luteal expression of soluble VEGFR-1 in the pig. Theriogenology. 71:1298–1306. 2009. View Article : Google Scholar : PubMed/NCBI
43	Kanthou C, Dachs GU, Lefley DV, Steele AJ, Coralli-Foxon C, Harris S, Greco O, Dos Santos SA, Reyes-Aldasoro CC, English WR and Tozer GM: Tumour cells expressing single VEGF isoforms display distinct growth, survival and migration characteristics. PLoS One. 9:e1040152014. View Article : Google Scholar : PubMed/NCBI
44	Coultas L, Chawengsaksophak K and Rossant J: Endothelial cells and VEGF in vascular development. Nature. 438:937–945. 2005. View Article : Google Scholar : PubMed/NCBI
45	Augustin HG, Koh GY, Thurston G and Alitalo K: Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol. 10:165–177. 2009. View Article : Google Scholar : PubMed/NCBI
46	Holash J, Maisonpierre P, Compton D, Boland P, Alexander CR, Zagzag D, Yancopoulos GD and Wiegand SJ: Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science. 284:1994–1998. 1999. View Article : Google Scholar : PubMed/NCBI
47	Jeansson M, Gawlik A, Anderson G, Li C, Kerjaschki D, Henkelman M and Quaggin SE: Angiopoietin-1 is essential in mouse vasculature during development and in response to injury. J Clin Invest. 121:2278–2289. 2011. View Article : Google Scholar : PubMed/NCBI