Final Report Summary - ADENOSINE (The role of adenosine in placental development and function)
Preeclampsia (PE) is a common hypertensive disorder of pregnancy, affecting 5-8 % of all pregnancies. There is currently no effective cure or treatment for this disorder, aside from prompt delivery of the placenta. As such, PE is a leading global cause of maternal and infant morbidity and mortality and responsible for 76 000 deaths each year. The pathophysiology of the disease is incompletely understood and a focus of perinatal research worldwide. The most accepted hypothesis states that placental hypoxia and dysfunction lead to the release of placental substances that cause maternal endothelial dysfunction and the clinical symptoms of the disease.
Therefore, the focus of this proposal was to investigate the role of the hypoxia-inducible signal adenosine in placental development using cell culture and villous explant culture models.
Using an immortalised first trimester human trophoblast cell line HTR8/SVneo our main results show that stimulation of adenosine A2B receptor reduced trophoblast migration at 2 % O2, 8 % O2 and 21 % O2 compared to untreated control cells. A2B adenosine receptor stimulation decreased phosphorylation of the mitogen activated protein kinases (MAPK) extracellular signal-regulated kinases (ERK1/2), SAPK / JNK and p38. A2B adenosine receptor activation also reduced proMMP-2 activity, MMP-2 mRNA levels and vascular endothelial growth factor (VEGF) expression. These data indicate A2B receptor activation blunts trophoblast migration possibly as a result of reduced activation of the MAPK signalling pathway and lower MMP-2 levels. Additional results show that hypoxia increases adenosine receptor A2A, A2B and HIF-1alpha expression of trophoblast cells, activation of the adenosine receptor A2B increases the proliferation of HTR8 / SVneo trophoblast cells at 2 % and 8 % oxygen but decreases proliferation of endothelial cells, blocking of the adenosine receptors A2A or A2B decreases invasion of trophoblast cells, stimulation of the A2B receptor shows no effect on angiogenic activity (tubule formation) of endothelial cells.
The investigations of the effect of adenosine receptor A2a and A2B activation or inhibition on placental amino acid transport show no association with placental system A amino acid transporter activity. However, system A amino acid transporter activity was oxygen dependent and reduced with decreasing oxygen concentrations.
Our data suggest a role for adenosine receptor A2B in placental development and possibly in the pathophysiology of PE. The identification of circulating agents, such as adenosine, that contribute to this pathology, along with their mechanisms of action, may provide a critical therapeutic target of intervention for the treatment of women at risk of developing PE. Future studies emanating from this project will further elucidate the mechanisms of adenosine action and its receptors in placental physiology.
Contact:
Priv.-Doz. Dr. med. Frauke von Versen-Höynck, MSc
Research Group Molecular Perinatology
Department of Obstetrics, Gynecology and Reproductive Medicine
Hannover Medical School
Carl-Neuberg-Str. 1
D- 30625 Hannover
Germany
Phone: +49-511-5326084 or 6074 Fax: +49-511-5326081
vonversen-hoeynck.frauke@mh-hannover.de
Therefore, the focus of this proposal was to investigate the role of the hypoxia-inducible signal adenosine in placental development using cell culture and villous explant culture models.
Using an immortalised first trimester human trophoblast cell line HTR8/SVneo our main results show that stimulation of adenosine A2B receptor reduced trophoblast migration at 2 % O2, 8 % O2 and 21 % O2 compared to untreated control cells. A2B adenosine receptor stimulation decreased phosphorylation of the mitogen activated protein kinases (MAPK) extracellular signal-regulated kinases (ERK1/2), SAPK / JNK and p38. A2B adenosine receptor activation also reduced proMMP-2 activity, MMP-2 mRNA levels and vascular endothelial growth factor (VEGF) expression. These data indicate A2B receptor activation blunts trophoblast migration possibly as a result of reduced activation of the MAPK signalling pathway and lower MMP-2 levels. Additional results show that hypoxia increases adenosine receptor A2A, A2B and HIF-1alpha expression of trophoblast cells, activation of the adenosine receptor A2B increases the proliferation of HTR8 / SVneo trophoblast cells at 2 % and 8 % oxygen but decreases proliferation of endothelial cells, blocking of the adenosine receptors A2A or A2B decreases invasion of trophoblast cells, stimulation of the A2B receptor shows no effect on angiogenic activity (tubule formation) of endothelial cells.
The investigations of the effect of adenosine receptor A2a and A2B activation or inhibition on placental amino acid transport show no association with placental system A amino acid transporter activity. However, system A amino acid transporter activity was oxygen dependent and reduced with decreasing oxygen concentrations.
Our data suggest a role for adenosine receptor A2B in placental development and possibly in the pathophysiology of PE. The identification of circulating agents, such as adenosine, that contribute to this pathology, along with their mechanisms of action, may provide a critical therapeutic target of intervention for the treatment of women at risk of developing PE. Future studies emanating from this project will further elucidate the mechanisms of adenosine action and its receptors in placental physiology.
Contact:
Priv.-Doz. Dr. med. Frauke von Versen-Höynck, MSc
Research Group Molecular Perinatology
Department of Obstetrics, Gynecology and Reproductive Medicine
Hannover Medical School
Carl-Neuberg-Str. 1
D- 30625 Hannover
Germany
Phone: +49-511-5326084 or 6074 Fax: +49-511-5326081
vonversen-hoeynck.frauke@mh-hannover.de
