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(Hypertension. 2009;53:959.)
© 2009 American Heart Association, Inc.

Original Articles

Vascular Contraction and Preeclampsia

Downregulation of the Angiotensin Receptor 1 by Hemopexin In Vitro

Winston W. Bakker; Rob H. Henning; Willem J. van Son; Maria G. van Pampus; Jan G. Aarnoudse; Klary E. Niezen-Koning; Theo Borghuis; Rianne M. Jongman; Harry van Goor; Klaas Poelstra; Gerjan Navis; Marijke M. Faas

From the Departments of Pathology and Laboratory Medicine (W.W.B., T.B., R.M.J., H.v.G.), Clinical Pharmacology (R.H.H.), Internal Medicine (W.J.v.S., G.N.), Obstetrics and Gynecology (M.G.v.P., J.G.A.), and Pediatrics (K.E.N.-K.) and Division of Medical Biology, Department of Pathology and Laboratory Medicine (M.M.F.), University Medical Center of Groningen and University of Groningen; and the Department of Pharmacokinetics and Drug Delivery (K.P.), University of Groningen, Groningen, The Netherlands.

Correspondence to Winston W. Bakker, Department of Pathology and Laboratory Medicine, University Medical Centre Groningen, Hanzeplein 1, PO Box 30001, 9700RB Groningen, The Netherlands. E-mail w.w.bakker{at}path.umcg.nl

During normal pregnancy, in contrast to preeclampsia, plasma hemopexin activity is increased together with a decreased vascular angiotensin II receptor (AT₁) expression. We now tested the hypothesis that hemopexin can downregulate the AT₁ receptor in vitro. Analysis of human monocytes or endothelial cells by flow cytometry showed decreased membrane density of AT₁ exclusively after incubation with active hemopexin, whereas in supernatants of these cell cultures, AT₁ molecules could be detected (dot blotting). Also, diminished AT₁ 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 AT₁ by hemopexin. In addition, functional loss of AT₁ 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 AT₁ 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 AT₁ 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 AT₁ receptor, promoting an expanded vascular bed. Inhibition of hemopexin activity during preeclampsia may result in an enhanced AT₁ receptor expression and a contracted vascular bed.

Key Words: pregnancy • preeclampsia • hemopexin activity • angiotensin receptor 1 • peripheral vascular resistance