Normal placentation occurs under low oxygen tensions yet hypoxia is also implicated in placental pathologies such as pre-eclampsia (PE). Hypoxia-inducible factors (HIFs), adenosine and tissue renin-angiotensin-system (RAS) are known to promote angiogenesis and vascularisation.  We hypothesised that placental adenosine A2AR receptor and HIF-1α would change through pregnancy in association with the RAS. Placentae were obtained from women undergoing elective surgical termination of pregnancy (TOP) at ≤10 weeks’ (early TOP) and >10 weeks’ (mid TOP) gestations; at delivery from normotensive (NT) and PE pregnancy. Results were compared to our previously reported data on the angiotensin receptors: AT1R, AT2R and AT4R.

Protein expression of both A2AR and HIF-1α was highest in early TOP and positively correlated through pregnancy (P<0.0001): expression was higher in PE than NT at delivery (P<0.0001 for both). The A2AR positively correlated with the AT4R in placentae in early pregnancy (r=0.53; P=0.035), but not in 3rd trimester samples. Our findings suggest a role for adenosine and RAS in promoting placentation and as a potential adaptation to poor placental perfusion in pre-eclampsia

Broughton Pipkin

Caniggia

Casanello

Escudero

F. Broughton Pipkin

Fredholm

Fung

Gant

H.D. Mistry

Hall

Hasko

J.N. Bulmer

Jauniaux

Kramar

Krick

L.O. Kurlak

Mistry

P.J. Williams

Patel

Poth

Rajakumar

Richard

Rodesch

Tebbs

Thakur

von Versen-Hoynck

Williams

Yoneyama

Kurlak, L.O.

Williams, Paula Juliet

Bulmer, Judith N.

Broughton Pipkin, Fiona

Mistry, Hiten D.

Nottingham ePrints

Kurlak, L.O. and Williams, Paula Juliet and Bulmer, Judith N. and Broughton Pipkin, Fiona and Mistry, Hiten D. (2015) Placental expression of adenosine A2A receptor and hypoxia inducible factor-1 alpha in early pregnancy, term and pre-eclamptic pregnancies: interactions with placental renin-angiotensin system. Placenta, 36 (5). pp. 611-613. ISSN 1532-3102 Access from the University of Nottingham repository: http://eprints.nottingham.ac.uk/44329/1/Adenosine%20A2a%20receptor%20in%20early%20pregnancy%20and%20PE%20_Accepted.pdfCopyright and reuse: The Nottingham ePrints service makes this work by researchers of the University of Nottingham available open access under the following conditions.This article is made available under the Creative Commons Attribution Non-commercial No Derivatives licence and may be reused according to the conditions of the licence.  For more details see: http://creativecommons.org/licenses/by-nc-nd/2.5/A note on versions: The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher’s version. Please see the repository url above for details on accessing the published version and note that access may require a subscription.For more information, please contact eprints@nottingham.ac.ukPlacental expression of adenosine A2A receptor and hypoxia inducible factor-1 alpha in early pregnancy, term and pre-eclamptic pregnancies; interactions with placental renin-angiotensin system Lesia O. Kurlak1*, Paula J. Williams2*, Judith N. Bulmer3, Fiona Broughton Pipkin1 & Hiten D. Mistry4 1Department of Obstetrics & Gynaecology, School of Medicine, University of Nottingham, NG5 1PB, UK; 2School of Veterinary Medicine & Science, Faculty of Medicine and Health Science, University of Nottingham, LE12 5RD, UK; 3Institute of Cellular Medicine, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK; 4Divison of Hypertension, Department of Nephrology, Hypertension and Clinical Pharmacology, University of Bern, CH-3010 Berne, Switzerland.  * Authors made equal contribution to this study.  Corresponding author’s address:   Dr. Lesia O. Kurlak  Division of Obstetrics & Gynaecology,   University of Nottingham,   1st Floor, Maternity Unit,   City Hospital,    Hucknall Road,   Nottingham,    NG5 1PB, UK   Lesia.kurlak@nottingham.ac.uk   Tel: +44(0)115 82 31955   Fax: +44 (0)115 82 31908  Running Title: Placental A2AR, HIF-1α and RAS receptors in early pregnancy and pre-eclampsia.  Abstract Normal placentation occurs under low oxygen tensions yet hypoxia is also implicated in placental pathologies such as pre-eclampsia (PE). Hypoxia-inducible factors (HIFs), adenosine and tissue renin-angiotensin-system (RAS) are known to promote angiogenesis and vascularisation.  We hypothesised that placental adenosine A2AR receptor and HIF-1α would change through pregnancy in association with the RAS. Placentae were obtained from women undergoing elective surgical termination of pregnancy (TOP) at ≤10 weeks’ (early TOP) and >10 weeks’ (mid TOP) gestations; at delivery from normotensive (NT) and PE pregnancy. Results were compared to our previously reported data on the angiotensin receptors: AT1R, AT2R and AT4R. Protein expression of both A2AR and HIF-1α was highest in early TOP and positively correlated through pregnancy (P<0.0001): expression was higher in PE than NT at delivery (P<0.0001 for both). The A2AR positively correlated with the AT4R in placentae in early pregnancy (r=0.53; P=0.035), but not in 3rd trimester samples. Our findings suggest a role for adenosine and RAS in promoting placentation and as a potential adaptation to poor placental perfusion in pre-eclampsia.     Introduction Adenosine modulates a number of physiological processes including promotion of angiogenesis, cell proliferation, inflammation, regulation of vascular tone and protection against oxidative stress [1]: hypoxia stimulates release of adenosine [2].  Normal placentation develops under low oxygen conditions [3] with oxygen sensing hypoxia-inducible factors (HIFs) regulating the transcription of genes that participate in angiogenesis and invasion enhancing vascularization.  Both angiotensin peptides, AngII and AngIV, acting through receptors AT2R and AT4R, have similar effects to adenosine in promoting angiogenesis, proliferation, inflammation and protection against oxidative stress [4]. In early pregnancy both AT2R and AT4R are highly expressed, contributing to normal placental development [5] including extravillious trophoblast invasion [6]. In PE, where impaired placentation leads to an inadequate feto-placental circulation and increased oxidative stress, maternal and umbilical venous adenosine [7] and placental HIF-1α concentrations [8, 9] are raised as is placental AT1R expression [6] whilst  conversely, AT4R expression is reduced [6]. The aims of this study were to 1) demonstrate the presence and distribution of the A2AR and HIF-1α in early TOP (8-10 weeks gestational age) when placental oxygen tension is low,mid (12-14 weeks gestational age) after spiral artery blood flow is established and at term in NT and PE placentae. 2) To relate these to the angiotensin receptors known to be involved in placentation.    Methods After local Ethical Committee approval and with appropriate informed consent, placental tissue identified by its macroscopic appearance, was dissected from products of conception obtained from women undergoing elective surgical termination of pregnancy (TOP) at 8-10 weeks (early TOP; n = 8; gestational age 8.8 ± 0.9 weeks [Mean ± S.D.]) and 12-14 weeks’ gestational age (mid TOP; n = 11; gestational age 12.7 ± 1.0 weeks). Placental samples were also taken at delivery in the third trimester from 11 women with normotensive pregnancy (39.1 ± 1.4 weeks) and 10 women with PE (37.6 ± 2.6 weeks) who underwent Caesarean section prior to labour.  We compared these observations with angiotensin receptor data previously obtained in these samples using identical methodology [6].   Immunohistochemical staining was performed using rabbit polyclonal antibodies (A2AR and HIF-1α (10 µg/ml), as previously described [6]. Rabbit IgG was used as negative controls. All slides were assessed by the same observer and quantified using the Positive Pixel Algorithm of Aperio ImageScope software [6, 10].   Results Both A2AR (Fig.1A) and HIF-1α (Fig. 1B) proteins were confined to villous syncytiotrophoblasts and cytotrophoblasts with immunochemical intensity being stronger in the syncytiotrophoblast outer layer of the villi than in the underlying cytotrophoblast layer. Expression of both proteins was highest at 8-10 weeks gestation,  decreasing at 12-14 weeks, and falling further to term in normotensive placentae (P<0.0001 for all; Fig. 1). However, for both proteins, placental expression was similar in placentae from mid-TOP and PE  P>0.05). Moreover, both proteins were higher in PE compared to controls (P<0.001). A very strong positive correlation was found between A2AR and HIF-1α in all groups overall throughout pregnancy (r = 0.85; P < 0.0001).  The protein expression of the RAS receptors has previously been reported [6]. Positive correlations were observed between A2AR and both AT2R (r = 0.52; P=0.033) and AT4R (r = 0.55; P=0.023) in placentae obtained before 20 weeks’ gestation. However, AT2R and AT4R expression were themselves strongly correlated at this gestational age (r = 0.485; P<0.002) and partial correlation analysis showed A2AR to be significantly correlated only with AT4R expression (r = 0.53; P=0.035; Fig. 2). No such correlation was found for the term normotensive or pre-eclamptic pregnancies. Placental expression of HIF-1α was independent of RAS receptor expression at all gestations.     Discussion This study demonstrates the expression and cellular localisation of both A2AR and HIF-1α spanning first trimester to term. We uniquely report a strong correlation between these proteins over this period.  The higher expression of A2AR and HIF-1α in PE, despite similar gestational ages to the NT pregnancies, suggests that this association is not purely a developmental phenomenon, but related to tissue oxygen status.  The correlation between A2AR with the angiotensin receptor - AT4R raises the possibility of a novel interaction of adenosine and the RAS during early placentation.  AT4R has already been implicated in the regulation of blood flow [11], being present in both endothelial [12] and smooth muscle cells [13]. Moreover, chronic hypoxia upregulates AT4R in the carotid body [14], with an increase in AngIV-induced intracellular [Ca2+]. Interestingly, adenosine also raises intracellular [Ca2+] via cyclic AMP under these conditions. Of note, activation of AT4R can produce endogenous vasodilatory nitric oxide via activation of endothelial nitric oxide synthase (eNOS) [15] and likewise, adenosine increases nitric oxide synthesis from feto-placental endothelium [16, 17]. The loss of the correlation between A2AR and AT4R in the term samples, whether NT or PE, is suggestive of a specific interaction during placental growth. There are a number of possible mechanisms to explore and future work is required to fully characterise the functional impact of A2AR, AT2R and AT4R both in early placental development and in relation to PE.   References 1. Hasko, G. and B.N. Cronstein, Adenosine: an endogenous regulator of innate immunity. Trends Immunol, 2004. 25(1): p. 33-9. 2. Poth, J.M., et al., Transcriptional control of adenosine signaling by hypoxia-inducible transcription factors during ischemic or inflammatory disease. J Mol Med (Berl), 2013. 91(2): p. 183-93. 3. Rodesch, F., et al., Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy. Obstet Gynecol, 1992. 80(2): p. 283-5. 4. Broughton Pipkin, F., The renin-angiotensin system in pre-eclampsia, in Pre-eclampsia, F. Lyall and M. Belfort, Editors. 2007, Cambridge University Press: Cambridge. p. 78-91. 5. Tebbs, C., M.K. Pratten, and F. Broughton Pipkin, Angiotensin II is a growth factor in the peri-implantation rat embryo. J Anat, 1999. 195 ( Pt 1): p. 75-86. 6. Williams, P.J., et al., Expression of AT1R, AT2R and AT4R and their roles in extravillous trophoblast invasion in the human. Placenta, 2010. 31(5): p. 448-55. 7. Yoneyama, Y., et al., Increased plasma adenosine concentrations and the severity of preeclampsia. Obstet Gynecol, 2002. 100(6): p. 1266-70. 8. Caniggia, I. and J.L. Winter, Adriana and Luisa Castellucci Award lecture 2001. Hypoxia inducible factor-1: oxygen regulation of trophoblast differentiation in normal and pre-eclamptic pregnancies--a review. Placenta, 2002. 23 Suppl A: p. S47-57. 9. Rajakumar, A., et al., Proteasomal activity in placentas from women with preeclampsia and intrauterine growth restriction: implications for expression of HIF-alpha proteins. Placenta, 2008. 29(3): p. 290-9. 10. Mistry, H.D., et al., Novel expression and regulation of voltage-dependent potassium channels in placentas from women with preeclampsia. Hypertension, 2011. 58(3): p. 497-504. 11. Kramar, E.A., J.W. Harding, and J.W. Wright, Angiotensin II- and IV-induced changes in cerebral blood flow. Roles of AT1, AT2, and AT4 receptor subtypes. Regul Pept, 1997. 68(2): p. 131-8. 12. Hall, K.L., et al., Characterization of a functional angiotensin IV receptor on coronary microvascular endothelial cells. Regul Pept, 1995. 58(3): p. 107-15. 13. Hall, K.L., et al., Identification and characterization of a novel angiotensin binding site in cultured vascular smooth muscle cells that is specific for the hexapeptide (3-8) fragment of angiotensin II, angiotensin IV. Regul Pept, 1993. 44(2): p. 225-32. 14. Fung, M.L., et al., Carotid Body AT(4) Receptor Expression and its Upregulation in Chronic Hypoxia. Open Cardiovasc Med J, 2007. 1: p. 1-7. 15. Patel, J.M., et al., Angiotensin IV receptor-mediated activation of lung endothelial NOS is associated with vasorelaxation. Am J Physiol, 1998. 275(6 Pt 1): p. L1061-8. 16. Casanello, P., C. Escudero, and L. Sobrevia, Equilibrative nucleoside (ENTs) and cationic amino acid (CATs) transporters: implications in foetal endothelial dysfunction in human pregnancy diseases. Curr Vasc Pharmacol, 2007. 5(1): p. 69-84. 17. Escudero, C. and L. Sobrevia, A hypothesis for preeclampsia: adenosine and inducible nitric oxide synthase in human placental microvascular endothelium. Placenta, 2008. 29(6): p. 469-83.     Figure Legends Figure 1: Immunohistochemical quantification and localization of A) A2AR and B) HIF-1α at 8-10 weeks gestation (A1 & B1), 12-14 weeks gestation (A2 & B2), term normotensive control (A3 & B3) and PE placentae (A4 & B4). (A5 & B5) demonstrates the negative control. Data are presented as median [IQR]; ***P < 0.0001. All photomicrographs taken at x200 magnification; positive staining is shown in brown, black arrows indicate villous cytotrophoblast cells and red arrows show villous syncytiotrophoblast cells.   Figure 2: Scatter plot illustrating the positive association between A2AR and AT4R in placentae < 20 weeks gestation (r = 0.53; P = 0.035).  

Placental expression of adenosine A2A receptor and hypoxia inducible factor-1 alpha in early pregnancy, term and pre-eclamptic pregnancies: interactions with placental renin-angiotensin system

Normal placentation occurs under low oxygen tensions yet hypoxia is also implicated in placental pathologies such as pre-eclampsia (PE). Hypoxia-inducible factors (HIFs), adenosine and tissue renin-angiotensin-system (RAS) are known to promote angiogenesis and vascularisation.  We hypothesised that placental adenosine A2AR receptor and HIF-1α would change through pregnancy in association with the RAS. Placentae were obtained from women undergoing elective surgical termination of pregnancy (TOP) at ≤10 weeks’ (early TOP) and >10 weeks’ (mid TOP) gestations; at delivery from normotensive (NT) and PE pregnancy. Results were compared to our previously reported data on the angiotensin receptors: AT1R, AT2R and AT4R.\ud
Protein expression of both A2AR and HIF-1α was highest in early TOP and positively correlated through pregnancy (P<0.0001): expression was higher in PE than NT at delivery (P<0.0001 for both). The A2AR positively correlated with the AT4R in placentae in early pregnancy (r=0.53; P=0.035), but not in 3rd trimester samples. Our findings suggest a role for adenosine and RAS in promoting placentation and as a potential adaptation to poor placental perfusion in pre-eclampsia

Name not available

Normal placentation occurs under low oxygen tensions yet hypoxia is also implicated in placental pathologies such as pre-eclampsia (PE). Hypoxia-inducible factors (HIFs), adenosine and tissue renin-angiotensin-system (RAS) are known to promote angiogenesis and vascularisation. We hypothesised that placental adenosine A2AR receptor and HIF-1α would change through pregnancy in association with the RAS. Placentae were obtained from women undergoing elective surgical termination of pregnancy (TOP) at ≤10 weeks’ (early TOP) and >10 weeks’ (mid TOP) gestations; at delivery from normotensive (NT) and PE pregnancy. Results were compared to our previously reported data on the angiotensin receptors: AT1R, AT2R and AT4R.Protein expression of both A2AR and HIF-1α was highest in early TOP and positively correlated through pregnancy (P<0.0001): expression was higher in PE than NT at delivery (P<0.0001 for both). The A2AR positively correlated with the AT4R in placentae in early pregnancy (r=0.53; P=0.035), but not in 3rd trimester samples. Our findings suggest a role for adenosine and RAS in promoting placentation and as a potential adaptation to poor placental perfusion in pre-eclampsia

Repository@Nottingham

Placental expression of adenosine A2A receptor and hypoxia inducible factor-1 alpha in early pregnancy, term and pre-eclamptic pregnancies; interactions with placental renin-angiotensin system Lesia O. Kurlak1*, Paula J. Williams2*, Judith N. Bulmer3, Fiona Broughton Pipkin1 & Hiten D. Mistry4 1Department of Obstetrics & Gynaecology, School of Medicine, University of Nottingham, NG5 1PB, UK; 2School of Veterinary Medicine & Science, Faculty of Medicine and Health Science, University of Nottingham, LE12 5RD, UK; 3Institute of Cellular Medicine, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK; 4Divison of Hypertension, Department of Nephrology, Hypertension and Clinical Pharmacology, University of Bern, CH-3010 Berne, Switzerland.  * Authors made equal contribution to this study.  Corresponding author’s address:   Dr. Lesia O. Kurlak  Division of Obstetrics & Gynaecology,   University of Nottingham,   1st Floor, Maternity Unit,   City Hospital,    Hucknall Road,   Nottingham,    NG5 1PB, UK   Lesia.kurlak@nottingham.ac.uk   Tel: +44(0)115 82 31955   Fax: +44 (0)115 82 31908  Running Title: Placental A2AR, HIF-1α and RAS receptors in early pregnancy and pre-eclampsia.  Abstract Normal placentation occurs under low oxygen tensions yet hypoxia is also implicated in placental pathologies such as pre-eclampsia (PE). Hypoxia-inducible factors (HIFs), adenosine and tissue renin-angiotensin-system (RAS) are known to promote angiogenesis and vascularisation.  We hypothesised that placental adenosine A2AR receptor and HIF-1α would change through pregnancy in association with the RAS. Placentae were obtained from women undergoing elective surgical termination of pregnancy (TOP) at ≤10 weeks’ (early TOP) and >10 weeks’ (mid TOP) gestations; at delivery from normotensive (NT) and PE pregnancy. Results were compared to our previously reported data on the angiotensin receptors: AT1R, AT2R and AT4R. Protein expression of both A2AR and HIF-1α was highest in early TOP and positively correlated through pregnancy (P<0.0001): expression was higher in PE than NT at delivery (P<0.0001 for both). The A2AR positively correlated with the AT4R in placentae in early pregnancy (r=0.53; P=0.035), but not in 3rd trimester samples. Our findings suggest a role for adenosine and RAS in promoting placentation and as a potential adaptation to poor placental perfusion in pre-eclampsia.     Introduction Adenosine modulates a number of physiological processes including promotion of angiogenesis, cell proliferation, inflammation, regulation of vascular tone and protection against oxidative stress [1]: hypoxia stimulates release of adenosine [2].  Normal placentation develops under low oxygen conditions [3] with oxygen sensing hypoxia-inducible factors (HIFs) regulating the transcription of genes that participate in angiogenesis and invasion enhancing vascularization.  Both angiotensin peptides, AngII and AngIV, acting through receptors AT2R and AT4R, have similar effects to adenosine in promoting angiogenesis, proliferation, inflammation and protection against oxidative stress [4]. In early pregnancy both AT2R and AT4R are highly expressed, contributing to normal placental development [5] including extravillious trophoblast invasion [6]. In PE, where impaired placentation leads to an inadequate feto-placental circulation and increased oxidative stress, maternal and umbilical venous adenosine [7] and placental HIF-1α concentrations [8, 9] are raised as is placental AT1R expression [6] whilst  conversely, AT4R expression is reduced [6]. The aims of this study were to 1) demonstrate the presence and distribution of the A2AR and HIF-1α in early TOP (8-10 weeks gestational age) when placental oxygen tension is low,mid (12-14 weeks gestational age) after spiral artery blood flow is established and at term in NT and PE placentae. 2) To relate these to the angiotensin receptors known to be involved in placentation.    Methods After local Ethical Committee approval and with appropriate informed consent, placental tissue identified by its macroscopic appearance, was dissected from products of conception obtained from women undergoing elective surgical termination of pregnancy (TOP) at 8-10 weeks (early TOP; n = 8; gestational age 8.8 ± 0.9 weeks [Mean ± S.D.]) and 12-14 weeks’ gestational age (mid TOP; n = 11; gestational age 12.7 ± 1.0 weeks). Placental samples were also taken at delivery in the third trimester from 11 women with normotensive pregnancy (39.1 ± 1.4 weeks) and 10 women with PE (37.6 ± 2.6 weeks) who underwent Caesarean section prior to labour.  We compared these observations with angiotensin receptor data previously obtained in these samples using identical methodology [6].   Immunohistochemical staining was performed using rabbit polyclonal antibodies (A2AR and HIF-1α (10 µg/ml), as previously described [6]. Rabbit IgG was used as negative controls. All slides were assessed by the same observer and quantified using the Positive Pixel Algorithm of Aperio ImageScope software [6, 10].   Results Both A2AR (Fig.1A) and HIF-1α (Fig. 1B) proteins were confined to villous syncytiotrophoblasts and cytotrophoblasts with immunochemical intensity being stronger in the syncytiotrophoblast outer layer of the villi than in the underlying cytotrophoblast layer. Expression of both proteins was highest at 8-10 weeks gestation,  decreasing at 12-14 weeks, and falling further to term in normotensive placentae (P<0.0001 for all; Fig. 1). However, for both proteins, placental expression was similar in placentae from mid-TOP and PE  P>0.05). Moreover, both proteins were higher in PE compared to controls (P<0.001). A very strong positive correlation was found between A2AR and HIF-1α in all groups overall throughout pregnancy (r = 0.85; P < 0.0001).  The protein expression of the RAS receptors has previously been reported [6]. Positive correlations were observed between A2AR and both AT2R (r = 0.52; P=0.033) and AT4R (r = 0.55; P=0.023) in placentae obtained before 20 weeks’ gestation. However, AT2R and AT4R expression were themselves strongly correlated at this gestational age (r = 0.485; P<0.002) and partial correlation analysis showed A2AR to be significantly correlated only with AT4R expression (r = 0.53; P=0.035; Fig. 2). No such correlation was found for the term normotensive or pre-eclamptic pregnancies. Placental expression of HIF-1α was independent of RAS receptor expression at all gestations.     Discussion This study demonstrates the expression and cellular localisation of both A2AR and HIF-1α spanning first trimester to term. We uniquely report a strong correlation between these proteins over this period.  The higher expression of A2AR and HIF-1α in PE, despite similar gestational ages to the NT pregnancies, suggests that this association is not purely a developmental phenomenon, but related to tissue oxygen status.  The correlation between A2AR with the angiotensin receptor - AT4R raises the possibility of a novel interaction of adenosine and the RAS during early placentation.  AT4R has already been implicated in the regulation of blood flow [11], being present in both endothelial [12] and smooth muscle cells [13]. Moreover, chronic hypoxia upregulates AT4R in the carotid body [14], with an increase in AngIV-induced intracellular [Ca2+]. Interestingly, adenosine also raises intracellular [Ca2+] via cyclic AMP under these conditions. Of note, activation of AT4R can produce endogenous vasodilatory nitric oxide via activation of endothelial nitric oxide synthase (eNOS) [15] and likewise, adenosine increases nitric oxide synthesis from feto-placental endothelium [16, 17]. The loss of the correlation between A2AR and AT4R in the term samples, whether NT or PE, is suggestive of a specific interaction during placental growth. There are a number of possible mechanisms to explore and future work is required to fully characterise the functional impact of A2AR, AT2R and AT4R both in early placental development and in relation to PE.   References 1. Hasko, G. and B.N. Cronstein, Adenosine: an endogenous regulator of innate immunity. Trends Immunol, 2004. 25(1): p. 33-9. 2. Poth, J.M., et al., Transcriptional control of adenosine signaling by hypoxia-inducible transcription factors during ischemic or inflammatory disease. J Mol Med (Berl), 2013. 91(2): p. 183-93. 3. Rodesch, F., et al., Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy. Obstet Gynecol, 1992. 80(2): p. 283-5. 4. Broughton Pipkin, F., The renin-angiotensin system in pre-eclampsia, in Pre-eclampsia, F. Lyall and M. Belfort, Editors. 2007, Cambridge University Press: Cambridge. p. 78-91. 5. Tebbs, C., M.K. Pratten, and F. Broughton Pipkin, Angiotensin II is a growth factor in the peri-implantation rat embryo. J Anat, 1999. 195 ( Pt 1): p. 75-86. 6. Williams, P.J., et al., Expression of AT1R, AT2R and AT4R and their roles in extravillous trophoblast invasion in the human. Placenta, 2010. 31(5): p. 448-55. 7. Yoneyama, Y., et al., Increased plasma adenosine concentrations and the severity of preeclampsia. Obstet Gynecol, 2002. 100(6): p. 1266-70. 8. Caniggia, I. and J.L. Winter, Adriana and Luisa Castellucci Award lecture 2001. Hypoxia inducible factor-1: oxygen regulation of trophoblast differentiation in normal and pre-eclamptic pregnancies--a review. Placenta, 2002. 23 Suppl A: p. S47-57. 9. Rajakumar, A., et al., Proteasomal activity in placentas from women with preeclampsia and intrauterine growth restriction: implications for expression of HIF-alpha proteins. Placenta, 2008. 29(3): p. 290-9. 10. Mistry, H.D., et al., Novel expression and regulation of voltage-dependent potassium channels in placentas from women with preeclampsia. Hypertension, 2011. 58(3): p. 497-504. 11. Kramar, E.A., J.W. Harding, and J.W. Wright, Angiotensin II- and IV-induced changes in cerebral blood flow. Roles of AT1, AT2, and AT4 receptor subtypes. Regul Pept, 1997. 68(2): p. 131-8. 12. Hall, K.L., et al., Characterization of a functional angiotensin IV receptor on coronary microvascular endothelial cells. Regul Pept, 1995. 58(3): p. 107-15. 13. Hall, K.L., et al., Identification and characterization of a novel angiotensin binding site in cultured vascular smooth muscle cells that is specific for the hexapeptide (3-8) fragment of angiotensin II, angiotensin IV. Regul Pept, 1993. 44(2): p. 225-32. 14. Fung, M.L., et al., Carotid Body AT(4) Receptor Expression and its Upregulation in Chronic Hypoxia. Open Cardiovasc Med J, 2007. 1: p. 1-7. 15. Patel, J.M., et al., Angiotensin IV receptor-mediated activation of lung endothelial NOS is associated with vasorelaxation. Am J Physiol, 1998. 275(6 Pt 1): p. L1061-8. 16. Casanello, P., C. Escudero, and L. Sobrevia, Equilibrative nucleoside (ENTs) and cationic amino acid (CATs) transporters: implications in foetal endothelial dysfunction in human pregnancy diseases. Curr Vasc Pharmacol, 2007. 5(1): p. 69-84. 17. Escudero, C. and L. Sobrevia, A hypothesis for preeclampsia: adenosine and inducible nitric oxide synthase in human placental microvascular endothelium. Placenta, 2008. 29(6): p. 469-83.     Figure Legends Figure 1: Immunohistochemical quantification and localization of A) A2AR and B) HIF-1α at 8-10 weeks gestation (A1 & B1), 12-14 weeks gestation (A2 & B2), term normotensive control (A3 & B3) and PE placentae (A4 & B4). (A5 & B5) demonstrates the negative control. Data are presented as median [IQR]; ***P < 0.0001. All photomicrographs taken at x200 magnification; positive staining is shown in brown, black arrows indicate villous cytotrophoblast cells and red arrows show villous syncytiotrophoblast cells.   Figure 2: Scatter plot illustrating the positive association between A2AR and AT4R in placentae < 20 weeks gestation (r = 0.53; P = 0.035).  

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Placental expression of adenosine A2A receptor and hypoxia inducible factor-1 alpha in early pregnancy, term and pre-eclamptic pregnancies: Interactions with placental renin-angiotensin system

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Placental expression of adenosine A2A receptor and hypoxia inducible factor-1 alpha in early pregnancy, term and pre-eclamptic pregnancies: interactions with placental renin-angiotensin system

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