Estrogen and progesterone play pivotal roles in endothelial progenitor cell proliferation

Reproductive Biology and Endocrinology

Keiichi Matsubara¹  Yuko Matsubara¹ 

[1] Department of Obstetrics and Gynecology, Ehime Prefectural Niihama Hospital, Hongo, Niihama, Ehime, 792-0042 Japan

关键词: ovarian hormones;    neovascularization;    menstrual cycle;   

Others  :  1151169
DOI  :  10.1186/1477-7827-10-2

 received in 2011-09-07, accepted in 2012-01-17,  发布年份 2012

【 摘 要 】

Background

It has been previously suggested that angiogenesis occurs during the menstrual cycle. Moreover, a rise in uterine blood flow is largely maintained by vasodilatation and substantial increases in angiogenesis. It is known that estradiol (E2) and progesterone (P4) are involved in angiogenesis. Recently, endothelial progenitor cells (EPCs) were found to be involved in neovascularization; however, their roles in uterine neovascularization have not been well characterized. We hypothesized that E2- or P4-mediated EPC proliferation plays important roles in uterine neovascularization during the menstrual cycle.

Methods

The number of EPCs in peripheral blood from subjects in the menstrual phase (n = 12), follicular phase (n = 8), and luteal phase (n = 16), was measured using flow cytometry. Peripheral blood mononuclear cells (PBMCs) were cultured for seven days with or without 17beta-estradiol (E2beta) or P4, followed by assessment of EPC proliferation based upon the uptake of acetylated low density lipoprotein (LDL) and lectin. The expression of estrogen receptor (ER) or progesterone receptor (PR) in EPCs was also evaluated using real-time PCR.

Results

E2beta and P4 significantly increased the proliferation of EPCs derived from the peripheral blood of subjects in menstrual phase, but not subjects in the luteal phase. In addition, the expression level of ERalpha was markedly higher than ERbeta in EPCs derived from women in menstrual phase.

Conclusions

EPC proliferation is induced during the menstrual phase and proliferation can be affected by estrogen through ERalpha activation.

【 授权许可】

   
2012 Matsubara and Matsubara; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Magness RR, Zheng J: Maternal Cardiovascular Alterations During Pregnancy. In Pediatrics and Perinatology. The Scientific Basis. 2nd edition. Edited by Gluckman PD, Heymann MA. Arnold Publishing, London; 1996:762-772.
• [2]Magness RR: Maternal cardiovascular and other physiologic responses to the endocrinology of pregnancy. In Endocrinology of Pregnancy. Volume 18. Fuller Bazer, Humana Press Inc, Totowa NJ; 1998::507-539.
• [3]Perrot-Applanat M, Deng M, Fernandez H, Lelaidier C, Meduri G, Bouchard P: Immunohistochemical localization of estradiol and progesterone receptors in human uterus throughout pregnancy: expression in endometrial blood vessels. J Clin Endocrinol Metab 1994, 78:216-224.
• [4]Jabbour HN, Kelly RW, Fraser HM, Critchley HO: Endocrine regulation of menstruation. Endocr Rev 2006, 27:17-46.
• [5]Mints M, Jansson M, Sadeghi B, Westgren M, Uzunel M, Hassan M, Palmblad J: Endometrial endothelial cells are derived from donor stem cells in a bone marrow transplant recipient. Hum Reprod 2008, 23:139-143.
• [6]Risau W, Flamme I: Vasculogenesis. Annu Rev Cell Dev Biol 1995, 11:73-91.
• [7]Murayama T, Tepper O, Silver M, Ma H, Losordo DW, Isner JM, Asahara T, Kalka C: Determination of bone marrow-derived endothelial progenitor cell significance in angiogenic growth factor-induced neovascularization in vivo. Exp Hematol 2002, 30:967-972.
• [8]Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M, Kearney M, Magner M, Isner JM: Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 1999, 85:221-228.
• [9]Perrot-Applanat M, Ancelin M, Buteau-Lozano H, Meduri G, Bausero P: Ovarian steroids in endometrial angiogenesis. Steroids 2000, 65:599-603.
• [10]Hyder SM, Stancel GM: Regulation of angiogenic growth factors in the female reproductive tract by estrogens and progestins. Mol Endocrinol 1999, 13:806-811.
• [11]Carr BR, Wilson JD: Disorders of the ovary and the female reproductive tract. In Harrison's Principles of Internal Medicine. 11th edition. Edited by Braunwald E, Isselbacher KJ, Petersdorf RG, Nilson JD, Martin JB, Fauci AS. New York: McGraw-Hill; 1987:1818-1837.
• [12]Baird DT, Fraser IS: Blood production and ovarian secretion rates of esuadiol-17β and estrone in women throughout the menstrual cycle. J Clin Endocrinol Metab 1974, 38:l009-1017.
• [13]King AG, Zheng J, Bird IM, Magness RR: Estrogen receptor (ER) -α and ER-β stimulation increases vascular endothelial growth factor secretion by ovine uterine artery endothelial cells. 35th Annual Meeting of the Society for the Study of Reproduction 2002.
• [14]Byers MJ, Chen DB, Phernetton TM, Bird IM, Magness RR: Endothelial Estrogen Receptor α and β Expression and Steroid Regulation in Ovine Uterine Arteries. 48th Annual Meeting of the Society for Gynecologic Investigation 2001.
• [15]Chen Z, Yuhanna IS, Galcheva-Gargova Z, Karas RH, Mendelsohn ME, Shaul PW: Estrogen receptor alpha mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J Clin Invest 1999, 103:401-406.
• [16]Morales DE, McGowan KA, Grant DS, Maheshwari S, Bhartiya D, Cid MC, Kleinman HK, Schnaper HW: Estrogen promotes angiogenic activity in human umbilical vein endothelial cells in vitro and in a murine model. Circulation 1995, 91:755-763.
• [17]Shekhar MPV, Werdell J, Tait L: Interaction with endothelial cells is a prerequisite for branching ductal-alveolar morphogenesis and hyperplasia of preneoplastic human breast epithelial cells: regulation by estrogen. Cancer Res 2000, 60:439-449.
• [18]Ruifrok WP, de Boer RA, Iwakura A, Silver M, Kusano K, Tio RA, Losordo DW: Estradiol-induced, endothelial progenitor cell-mediated neovascularization in male mice with hind-limb ischemia. Vasc Med 2009, 14:29-36.
• [19]Ma W, Tan J, Matsumoto H, Robert B, Abrahamson DR, Das SK, Dey SK: Adult tissue angiogenesis: Evidence for negative regulation by estrogen in the uterus. Mol Endocrinol 2001, 15:1983-1992.
• [20]Rupnow HL, Phernetton TM, Shaw CE, Modrick ML, Bird IM, Magness RR: Endothelial vasodilator production by uterine and systemic arteries. VII. Estrogen and progesterone effects on eNOS. Am J Physiol Heart Circ Physiol 2001, 280:H1699-H1705.
• [21]Levine RL, Chen S-J, Durand J, Chen Y-F, Oparil S: Medroxyprogesterone attenuates estrogen-mediated inhibition of neointima formation after balloon injury of the rat carotid artery. Circulation 1996, 94:2221-2227.
• [22]McDonnell DP, Clemm DL, Hermann T, Goldman ME, Pike JW: Analysis of estrogen receptor function in vitro reveals three distinct classes of antiestrogens. Mol Endocrinol 1995, 9:659-669.
• [23]Resnik R, Brink GW, Plumer MH: The effect of progesterone on estrogen-induced uterine blood flow. Am J Obstet Gynecol 1977, 128:251-254.
• [24]Magness RR, Phernetton TM, Zheng J: Systemic and uterine blood flow distribution during prolonged infusion of 17β-estradiol. Am J Physiol 1998, 275(Heart Circ Physiol):H731-H743.
• [25]Kalka C, Masuda H, Takahashi T, Kalka-Moll WM, Silver M, Kearney M, Li T, Isner JM, Asahara T: Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci USA 2000, 28:3422-3427.
• [26]Pan Q, Luo X, Toloubeydokhti T, Chegini N: The expression profile of micro-RNA in endometrium and endometriosis and the influence of ovarian steroids on their expression. Mol Hum Reprod 2007, 13:797-806.
• [27]Peichev M, Naiyer A, Pereira D, Zhu Z, Lane WJ, Williams M, Oz MC, Hicklin DJ, Witte L, Moore MA, Rafii S: Expression of VEGFR-2 and AC133 by circulating human CD34+ cells identifies a population of functional endothelial precursors. Blood 2000, 95:952-958.
• [28]Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M, Kearne M, Magner M, Isner JM: Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 1999, 85:221-228.
• [29]Murayama T, Tepper O, Silver M, Ma H, Losordo DW, Isner JM, Asahara T, Kalka C: Determination of bone marrow-derived endothelial progenitor cell significance in angiogenic growth factor-induced neovascularization in vivo. Exp Hematol 2002, 30:967-972.
• [30]Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM, Leri A, Anversa P: Bone marrow cells regenerate infarcted myocardium. Nature 2001, 410:701-705.
• [31]Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M, Kearne M, Magner M, Isner JM: Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 1999, 85:221-228.
• [32]Iwakura A, Luedemann C, Shastry S, Hanley A, Kearney M, Aikawa R, Isner JM, Asahara T, Losordo DW: Estrogen-mediated, endothelial nitric oxide synthase-dependent mobilization of bone marrow-derived endothelial progenitor cells contributes to reendothelialization after arterial injury. Circulation 2003, 108:3115-3121.
• [33]Taylor A, Al-Azzawi F: Immunolocalisation of oestrogen receptor beta in human tissues. J Mol Endocrinol 2000, 24:145-155.
• [34]Gussin H, Bischoff F, Hoffman R, Elias S: Endothelial precursor cells in the peripheral blood of pregnant women. J Soc Gynecol Invest 2000, 9:357-361.
• [35]Ottersbach K, Dzierzak E: The murine placenta contains hematopoietic stem cells within the vascular labyrinth region. Dev Cell 2005, 8:377-387.
• [36]Matsubara K, Abe E, Matsubara Y, Kameda K, Ito M: Circulating endothelial progenitor cells during normal pregnancy and pre-eclampsia. ARJI 2006, 56:1-7.
• [37]Lemieux C, Cloutier I, Tanguay JF: Menstrual cycle influences endothelial progenitor cell regulation: a link to gender differences in vascular protection? Int J Cardiol 2009, 136:200-210.
• [38]Iwakura A, Shastry S, Luedemann C, Hamada H, Kawamoto A, Kishore R, Zhu Y, Qin G, Silver M, Thorne T, Eaton L, Masuda H, Asahara T, Losordo DW: Estradiol enhances recovery after myocardial infarction by augmenting incorporation of bone marrow-derived endothelial progenitor cells into sites of ischemia-induced neovascularization via endothelial nitric oxide synthase-mediated activation of matrix metalloproteinase-9. Circulation 2006, 113:1605-1614.
• [39]Hamada H, Kim MK, Iwakura A, Ii M, Thorne T, Qin G, Asai J, Tsutsumi Y, Sekiguchi H, Silver M, Wecker A, Bord E, Zhu Y, Kishore R, Losordo DW: Estrogen receptors alpha and beta mediate contribution of bone marrow-derived endothelial progenitor cells to functional recovery after myocardial infarction. Circulation 2006, 114:2261-2270.
• [40]Strehlow K, Werner N, Berweiler J, Link A, Dirnagl U, Priller J, Laufs K, Ghaeni L, Milosevic M, Böhm M, Nickenig G: Estrogen increases bone marrow-derived endothelial progenitor cell production and diminishes neointima formation. Circulation 2003, 107:3059-3065.
• [41]Nakamura J, Lu Q, Aberdeen G, Albrecht E, Brodie A: The effect of estrogen on aromatase and vascular endothelial growth factor messenger ribonucleic acid in the normal nonhuman primate mammary gland. J Clin Endocrinol Metab 1999, 84:1432-1437.
• [42]Dong L, Kang L, Ding L, Chen Q, Bai J, Gu R, Li L, Xu B: Insulin modulates ischemia-induced endothelial progenitor cell mobilization and neovascularization in diabetic mice. Microvasc Res 2011, 82:227-236.
• [43]Albrecht E, Robb V, Pepe G: Regulation of placental vascular endothelial growth/permeability factor expression and angiogenesis by estrogen during early baboon pregnancy. J Clin Endocrinol Metab 2004, 89:5803-5809.
• [44]Carnegie JA, Robertson HA: Conjugated and unconjugated estrogens in fetal and maternal fluids of the pregnant ewe: a possible role for estrone sulfate during early pregnancy. Biol Reprod 1978, 19:202-211.
• [45]Flamme I, Risau W: Induction of vasculogenesis and hematopoiesis in vitro. Development 1992, 116:435-459.
• [46]Imanishi T, Kobayashi K, Hano T, Nishio I: Effect of estrogen on differentiation and senescence in endothelial progenitor cells derived from bone marrow in spontaneously hypertensive rats. Hypertens Res 2005, 28:763-772.