Expression and contribution of the HIF‑1α/VEGF signaling pathway to luteal development and function in pregnant rats

Wu,Lixiang; Zhang,Zhenghong; Pan,Xiaoyan; Wang,Zhengchao

doi:10.3892/mmr.2015.4268

Expression and contribution of the HIF‑1α/VEGF signaling pathway to luteal development and function in pregnant rats

Authors:
- Lixiang Wu
- Zhenghong Zhang
- Xiaoyan Pan
- Zhengchao Wang
View Affiliations

Affiliations: Provincial Key Laboratory for Developmental Biology and Neurosciences, College of Life Sciences, Fujian Normal University, Fuzhou, Fujian 350108, P.R. China, Department of Histology and Embryology, Jilin Medical College, Jilin, Jilin 132013, P.R. China
Published online on: August 28, 2015 https://doi.org/10.3892/mmr.2015.4268
Pages: 7153-7159

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Vascular endothelial growth factor (VEGF) is vital in normal and abnormal angiogenesis in the ovary, particularly during the early development of the corpus luteum in the ovary. However, the molecular regulation of the expression VEGF during luteal development in vivo remains to be fully elucidated. As the expression of VEGF is mediated by hypoxia‑inducible factor (HIF)‑1α in luteal cells cultured in vitro, determined in our previous study, the present study was performed to confirm the hypothesis that HIF‑1α is induced and then regulates the expression of VEGF and VEGF‑dependent luteal development/function in vivo. This was investigated using a pregnant rat model treated with a small‑molecule inhibitor of HIF‑1α, echinomycin (Ech). The development of the corpus luteum in the pregnant rat ovary was identified via performing assays of the serum progesterone, testosterone and estradiol concentrations by radioimmunoassay, accompanied with determination of the changes in the expression levels of HIF‑1α and VEGF by reverse transcription‑quantitative polymerase chain reaction at different days of the developmental process. On day 5, serum progesterone levels were markedly increased, whereas serum levels of testosterone and estradiol did not change significantly. On day 17, the highest level of serum progesterone was observed, however, this was not the case for testosterone and estradiol. Further analysis of the expression levels of HIF‑1α and VEGF revealed that their changes were consistent with the changes in serum levels of progesterone, which occurred in the development of the corpus luteum in the ovaries of pregnant rats. Further investigation demonstrated that Ech inhibited luteal development through inhibiting the expression of VEGF, mediated by HIF‑1α, and subsequent luteal function, which was determined by detecting changes in serum progesterone on days 8 and 14. Taken together, these results demonstrated that HIF‑1α‑mediated expression of VEGF may be one of the important mechanisms regulating ovarian luteal development in mammals in vivo, which may provide novel strategies in treatment for fertility control and for certain types of ovarian dysfunction, including polycystic ovarian syndrome, ovarian hyperstimulation syndrome and ovarian neoplasia.

View Figures

View References

1	Young FM, Rodger FE, Illingworth PJ and Fraser HM: Cell proliferation and vascular morphology in the marmoset corpus luteum. Hum Reprod. 15:557–66. 2000. View Article : Google Scholar : PubMed/NCBI
2	Wulff C, Dickson SE, Duncan WC and Fraser HM: Angiogenesis in the human corpus luteum: Simulated early pregnancy by HCG treatment is associated with both angiogenesis and vessel stabilization. Hum Reprod. 16:2515–2524. 2001. View Article : Google Scholar : PubMed/NCBI
3	Fraser HM, Bell J, Wilson H, Taylor PD, Morgan K, Abderson RA and Duncan WC: Localization and quantification of cyclic changes in the expression of endocrine gland vascular endothelial growth factor in the human corpus luteum. J Clin Endocrinol Metab. 90:427–434. 2005. View Article : Google Scholar
4	Fraser HM and Duncan WC: Vascular morphogenesis in the primate ovary. Angiogenesis. 8:101–116. 2005. View Article : Google Scholar : PubMed/NCBI
5	Nishimura R and Okuda K: Hypoxia is important for establishing vascularization during corpus luteum formation in cattle. J Reprod Dev. 56:110–116. 2010. View Article : Google Scholar
6	Amselgruber WM, Schäfer M and Sinowatz F: Angiogenesis in the bovine corpus luteum: An immunocytochemical and ultra-structural study. Anat Histol Embryol. 28:157–166. 1999. View Article : Google Scholar : PubMed/NCBI
7	Semenza GL: HIF-1: Mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol. 88:1474–1480. 2000.PubMed/NCBI
8	Semenza GL: Expression of hypoxia-inducible factor 1: Mechanisms and consequences. Biochem Pharmacol. 59:47–53. 2000. View Article : Google Scholar
9	Zhang Z, Yin D and Wang Z: Contribution of hypoxia-inducible factor-1α to transcriptional regulation of vascular endothelial growth factor in bovine developing luteal cells. Anim Sci J. 82:244–250. 2011. View Article : Google Scholar : PubMed/NCBI
10	Molitoris KH, Kazi AA and Koos RD: Inhibition of oxygen-induced hypoxia-inducible factor-1alpha degradation unmasks estradiol induction of vascular endothelial growth factor expression in ECC-1 cancer cells in vitro. Endocrinology. 150:5405–5414. 2009. View Article : Google Scholar : PubMed/NCBI
11	Miyazawa M, Yasuda M, Fujita M, Hirabayashi K, Hirasawa T, Kajiwara H, Muramatsu T, Miyazaki S, Harasawa M, Matsui N, et al: Granulosa cell tumor with activated mTOR-HIF-1alpha-VEGF pathway. J Obstet Gynaecol Res. 36:448–453. 2000. View Article : Google Scholar
12	Critchley HO, Osei J, Henderson TA, Boswell L, Sales KJ, Jabbour HN and Hirani N: Hypoxia-inducible factor-1alpha expression in human endometrium and its regulation by prostaglandin E-series prostanoid receptor 2 (EP2). Endocrinology. 147:744–753. 2006. View Article : Google Scholar
13	Neulen J, Yan Z, Raczek S, Weindel K, Keck C, Weich HA, Marmé D and Breckwoldt M: Human chorionic gonadotropin-dependent expression of vascular endothelial growth factor/vascular permeability factor in human granulosa cells: Importance in ovarian hyperstimulation syndrome. J Clin Endocrinol Metab. 80:1967–1971. 1995.PubMed/NCBI
14	Lee A, Christenson LK, Patton PE, Burry KA and Stouffer RL: Vascular endothelial growth factor production by human luteinized granulosa cells in vitro. Hum Reprod. 12:2756–2761. 1997. View Article : Google Scholar
15	Shimizu T, Jayawardana BC, Tetsuka M and Miyamoto A: Differential effect of follicle-stimulating hormone and estradiol on expressions of vascular endothelial growth factor (VEGF) 120, VEGF164 and their receptors in bovine granulosa cells. J Reprod Dev. 53:105–112. 2007. View Article : Google Scholar
16	Shimizu T and Miyamoto A: Progesterone induces the expression of vascular endothelial growth factor (VEGF) 120 and Flk-1, its receptor, in bovine granulosa cells. Anim Reprod Sci. 102:228–237. 2007. View Article : Google Scholar : PubMed/NCBI
17	van den Driesche S, Myers M, Gay E, Thong KJ and Duncan WC: HCG up-regulates hypoxia inducible factor-1 alpha in luteinized granulosa cells: Implications for the hormonal regulation of vascular endothelial growth factor A in the human corpus luteum. Mol Hum Reprod. 14:455–464. 2008. View Article : Google Scholar : PubMed/NCBI
18	Khandrika L, Lieberman R, Koul S, Kumar B, Maroni P, Chandhoke R, Meacham RB and Koul HK: Hypoxia-associated p38 mitogen-activated protein kinase-mediated androgen receptor activation and increased HIF-1alpha levels contribute to emergence of an aggressive phenotype in prostate cancer. Oncogene. 28:1248–1260. 2009. View Article : Google Scholar : PubMed/NCBI
19	Redmer DA and Reynolds LP: Angiogenesis in the ovary. Rev Reprod. 1:182–192. 1996. View Article : Google Scholar : PubMed/NCBI
20	Fraser HM and Wulff C: Angiogenesis in the primate ovary. Reprod Fertil Dev. 13:557–566. 2001. View Article : Google Scholar
21	Fraser HM and Wulff C: Angiogenesis in the corpus luteum. Reprod Biol Endocrinol. 1:882003. View Article : Google Scholar : PubMed/NCBI
22	Tamanini C and De Ambrogi M: Angiogenesis in developing follicle and corpus luteum. Reprod Domest Anim. 39:206–216. 2004. View Article : Google Scholar : PubMed/NCBI
23	Koos RD: Increased expression of vascular endothelial growth/permeability factor in the rat ovary following an ovulatory gonadotropin stimulus: Potential roles in follicle rupture. Biol Reprod. 52:1426–1435. 1995. View Article : Google Scholar : PubMed/NCBI
24	Nishimura R, Sakumoto R, Tatsukawa Y, Acosta TJ and Okuda K: Oxygen concentration is an important factor for modulating progesterone synthesis in bovine corpus luteum. Endocrinology. 147:4273–4280. 2006. View Article : Google Scholar : PubMed/NCBI
25	Zhang Z, Yu D, Yin D and Wang Z: Activation of PI3K/mTOR signaling pathway contributes to induction of vascular endothelial growth factor by hCG in bovine developing luteal cells. Anim Reprod Sci. 125:42–48. 2011. View Article : Google Scholar : PubMed/NCBI
26	Zhang Z, Pang X, Tang Z, Yin D and Wang Z: Overexpression of hypoxia-inducible factor prolyl hydoxylase-2 attenuates hypoxia-induced vascular endothelial growth factor expression in luteal cells. Mol Med Report. 12:3809–3814. 2015.
27	Wang Z, Tang L, Zhu Q, Yi F, Zhang F, Li PL and Li N: Hypoxia-inducible factor-1α contributes to the profibrotic action of angiotensin II in renal medullary interstitial cells. Kidney Int. 79:300–310. 2011. View Article : Google Scholar :
28	Wang Z, Zhu Q, Li PL, Dhaduk R, Zhang F, Gehr TW and Li N: Silencing of hypoxia-inducible factor-1α gene attenuates chronic ischemic renal injury in two-kidney, one-clip rats. Am J Physiol Renal Physiol. 306:1236–1242. 2014. View Article : Google Scholar
29	Wang Z, Zhu Q, Xia M, Li PL, Hinton SJ and Li N: Hypoxia-inducible factor prolylhydroxylase 2 senses high-salt intake to increase hypoxia inducible factor 1alpha levels in the renal medulla. Hypertension. 55:1129–1136. 2010. View Article : Google Scholar : PubMed/NCBI
30	Kaczmarek MM, Schams D and Ziecik AJ: Role of vascular endothelial growth factor in ovarian physiology-An overview. Reprod Biol. 5:111–136. 2005.PubMed/NCBI
31	Ravindranath N, Little-Ihrig L, Phillips HS, Ferrara N and Zeleznik AJ: Vascular endothelial growth factor messenger ribonucleic acid expression in the primate ovary. Endocrinology. 131:254–260. 1992.PubMed/NCBI
32	Christenson LK and Stouffer RL: Follicle-stimulating hormone and luteinizing hormone/chorionic gonadotropin stimulation of vascular endothelial growth factor production by macaque granulosa cells from pre- and periovulatory follicles. J Clin Endocrinol Metab. 82:2135–2142. 1997.PubMed/NCBI
33	Endo T, Kitajima Y, Nishikawa A, Manase K, Shibuya M and Kudo R: Cyclic changes in expression of mRNA of vascular endothelial growth factor, its receptors Flt-1 and KDR/Flk-1 and Ets-1 in human corpora lutea. Fertil Steril. 76:762–768. 2001. View Article : Google Scholar : PubMed/NCBI
34	Tesone M, Stouffer RL, Borman SM, Hennebold JD and Molskness TA: Vascular endothelial growth factor (VEGF) production by the monkey corpus luteum during the menstrual cycle: Isoform-selective messenger RNA expression in vivo and hypoxia-regulated protein secretion in vitro. Biol Reprod. 73:927–934. 2005. View Article : Google Scholar : PubMed/NCBI
35	Tropea A, Miceli F, Minici F, Tiberi F, Orlando M, Gangale MF, Romani F, Catino S, Mancuso S, Navarra P, et al: Regulation of vascular endothelial growth factor synthesis and release by human luteal cells in vitro. J Clin Endocrinol Metab. 91:2303–2309. 2006. View Article : Google Scholar : PubMed/NCBI
36	Fraser HM, Wilson H, Wulff C, Rudge JS and Wiegand SJ: Administration of vascular endothelial growth factor Trap during the 'post-angiogenic' period of the luteal phase causes rapid functional luteolysis and selective endothelial cell death in the marmoset. Reproduction. 132:589–600. 2006. View Article : Google Scholar : PubMed/NCBI
37	Duncan WC, van den Driesche S and Fraser HM: Inhibition of vascular endothelial growth factor in the primate ovary up-regulates hypoxia-inducible factor-1alpha in the follicle and corpus luteum. Endocrinology. 149:3313–3320. 2008. View Article : Google Scholar : PubMed/NCBI
38	Nastri CO, Ferriani RA, Rocha IA and Martins WP: Ovarian hyperstimulation syndrome: Pathophysiology and prevention. J Assist Reprod Genet. 27:121–128. 2010. View Article : Google Scholar : PubMed/NCBI
39	Fraser HM and Lunn SF: Angiogenesis and its control in the female reproductive system. Br Med Bull. 56:787–797. 2000. View Article : Google Scholar Duncan WC, van den Driesche S and Fraser HM: Inhibition of vascular endothelial growth factor in the primate ovary up-regulates hypoxia-inducible factor-1alpha in the follicle and corpus luteum. Endocrinology. 149:3313–3320. 2008. View Article : Google Scholar : PubMed/NCBI
40	Wang GL, Jiang BH, Rue EA and Semenza GL: Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA. 92:5510–5514. 1995. View Article : Google Scholar : PubMed/NCBI
41	Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM, Simons JW and Semenza GL: Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: Implications for tumor angiogenesis and therapeutics. Cancer Res. 60:1541–1545. 2000.PubMed/NCBI
42	Yaba A, Bianchi V, Borini A and Johnson J: A putative mitotic checkpoint dependent on mTOR function controls cell proliferation and survival in ovarian granulosa cells. Reprod Sci. 15:128–138. 2008. View Article : Google Scholar : PubMed/NCBI
43	Miyazawa M, Yasuda M, Fujita M, Kajiwara H, Hirabayashi K, Takekoshi S, Hirasawa T, Murakami M, Ogane N, Kiguchi K, et al: Therapeutic strategy targeting the mTOR-HIF-1alpha-VEGF pathway in ovarian clear cell adenocarcinoma. Pathol Int. 59:19–27. 2009. View Article : Google Scholar : PubMed/NCBI
44	Kazi AA, Jones JM and Koos RD: Chromatin immunoprecipitation analysis of gene expression in the rat uterus in vivo: Estrogen-induced recruitment of both estrogen receptor alpha and hypoxia-inducible factor 1 to the vascular endothelial growth factor promoter. Mol Endocrinol. 19:2006–2019. 2005. View Article : Google Scholar : PubMed/NCBI
45	Kazi AA and Koos RD: Estrogen-induced activation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor expression, and edema in the uterus are mediated by the phosphatidylinositol 3-kinase/Akt pathway. Endocrinology. 148:2363–2374. 2007. View Article : Google Scholar : PubMed/NCBI
46	Chan DA and Giaccia AJ: PHD2 in tumour angiogenesis. Br J Cancer. 103:1–5. 2010. View Article : Google Scholar : PubMed/NCBI