Vascular contraction and preeclampsia: downregulation of the Angiotensin receptor 1 by hemopexin in vitro.
During normal pregnancy, in contrast to preeclampsia, plasma hemopexin activity is increased together with a decreased vascular angiotensin II receptor (AT(1)) expression. We now tested the hypothesis that hemopexin can downregulate the AT(1) receptor in vitro. Analysis of human monocytes or endothelial cells by flow cytometry showed decreased membrane density of AT(1) exclusively after incubation with active hemopexin, whereas in supernatants of these cell cultures, AT(1) molecules could be detected (dot blotting). Also, diminished AT(1) was observed in endothelial cell lysates after contact with hemopexin (Western blotting). Hemopexin also induced extracellular signal-regulated kinase 1/2 pathway inhibition in cells after stimulation with angiotensin II in vitro, indicating downregulation of AT(1) by hemopexin. In addition, functional loss of AT(1) occurred after incubation of rat aortic rings with active hemopexin, as reflected by decreased contraction of the aortic rings on stimulation with angiotensin II. It was further demonstrated that plasma from normal pregnant women decreased the AT(1) receptor expression on monocytes as compared with plasma from nonpregnant women or preeclamptic women. Finally, it was shown that plasma hemopexin activity increases during normal gestation from week 10 onward. We concluded that active hemopexin is able to downregulate the AT(1) receptor in human monocytes, endothelial cells, and rat aortic rings. We propose that the physiological role of enhanced hemopexin activity during healthy pregnancy is to downregulate the vascular AT(1) receptor, promoting an expanded vascular bed. Inhibition of hemopexin activity during preeclampsia may result in an enhanced AT(1) receptor expression and a contracted vascular bed.
Bakker
Winston W
WW
Department of Pathology and Laboratory Medicine, University Medical Centre Groningen, Groningen, The Netherlands. w.w.bakker@path.umcg.nl
Henning
Rob H
RH
van Son
Willem J
WJ
van Pampus
Maria G
MG
Aarnoudse
Jan G
JG
Niezen-Koning
Klary E
KE
Borghuis
Theo
T
Jongman
Rianne M
RM
van Goor
Harry
H
Poelstra
Klaas
K
Navis
Gerjan
G
Faas
Marijke M
MM
D000704:Analysis of Variance; D015153:Blotting, Western; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D005260:Female; D006466:Hemopexin / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D011225:Pre-Eclampsia / Q000097:blood; D011247:Pregnancy; D011336:Probability; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism*; D012016:Reference Values; D012307:Risk Factors; D012680:Sensitivity and Specificity; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
D044140:Receptor, Angiotensin, Type 1; D006466:Hemopexin