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This Article Full Text Full Text (PDF) All Versions of this Article: 296/3/H745    most recent 00861.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Stennett, A. K. Articles by Khalil, R. A. Search for Related Content PubMed PubMed Citation Articles by Stennett, A. K. Articles by Khalil, R. A.

Increased vascular angiotensin type 2 receptor expression and NOS-mediated mechanisms of vascular relaxation in pregnant rats

Division of Vascular Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

Submitted 6 August 2008 ; accepted in final form 12 January 2009

Normal pregnancy is associated with reduced blood pressure (BP) and decreased pressor response to vasoconstrictors, even though the renin-angiotensin system is upregulated. Angiotensin II (ANG II) activates both angiotensin type 1 receptors (AT₁Rs) and angiotensin type 2 receptors (AT₂Rs). Although the role of the AT₁R in vascular contraction is well documented, the role of the AT₂R in vascular relaxation, particularly during pregnancy, is less clear. It was hypothesized that the decreased BP and vasoconstriction during pregnancy was, at least in part, due to changes in AT₂R amount, distribution, and/or postreceptor mechanisms of vascular relaxation. To test this hypothesis, systolic BP was measured in virgin and pregnant (day 19) Sprague-Dawley rats. Isometric contraction/relaxation was measured in isolated aortic rings, and nitric oxide (NO) production was measured using 4-amino-5-methylamino-2',7'-difluorescein fluorescence. AT₁R and AT₂R mRNA expression and protein amount were measured in tissue homogenates using real-time RT-PCR and Western blots, and their local distribution was visualized in cryosections using immunohistochemistry and immunofluorescence. BP was lower in pregnant than virgin rats. Phenylephrine (Phe) caused concentration-dependent contraction that was reduced in the aorta of pregnant compared with virgin rats. Treatment with the AT₂R antagonist PD-123319 caused greater enhancement of Phe contraction, and the AT₂R agonist CGP-42112A caused greater relaxation of Phe contraction in the aorta of pregnant than virgin rats. ANG II plus the AT₁R blocker losartan induced greater NO production in the aorta of pregnant than virgin rats. RT-PCR revealed increased mRNA expression of vascular endothelial NO synthase (eNOS), little change in AT₁Rs, and increased AT₂Rs in pregnant compared with virgin rats. Western blots revealed an increased protein amount of activated phospho-eNOS, little change in AT₁Rs, and increased AT₂Rs in pregnant compared with virgin rats. Immunohistochemistry and immunofluorescence analysis in aortic sections of virgin rats revealed abundant AT₁R staining in tunica media that largely colocalized with actin in vascular smooth muscle and less AT₂Rs mainly in the tunica intima and endothelium. In pregnant rats, AT₁R staining in the smooth muscle layer and adventitia was reduced, and endothelial AT₂R staining was enhanced. These data suggest an enhanced AT₂R-mediated vascular relaxation pathway involving increased expression/activity of endothelial AT₂Rs and increased postreceptor activated phospho-eNOS, which may contribute to the decreased BP during pregnancy.

endothelium; nitric oxide; nitric oxide synthase; vascular smooth muscle; blood pressure