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This Article Full Text Full Text (PDF) All Versions of this Article: 288/4/F763    most recent 00323.2004v1 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 Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Andresen, B. T. Articles by Romero, G. G. Search for Related Content PubMed PubMed Citation Articles by Andresen, B. T. Articles by Romero, G. G.

AT₂ receptors cross talk with AT₁ receptors through a nitric oxide- and RhoA-dependent mechanism resulting in decreased phospholipase D activity

²Department of Pharmacology, University of Pittsburgh, and ³Center for Clinical Pharmacology, School of Medicine, Pittsburgh, Pennsylvania; and ¹Department of Pediatrics, Georgetown University Medical Center, Washington, District of Columbia

Submitted 25 August 2004 ; accepted in final form 26 November 2004

ANG II activation of phospholipase D (PLD) is required for ERK and NAD(P)H oxidase activation, both of which are involved in hypertension. Previous findings demonstrate that ANG II stimulates PLD activity through AT₁ receptors in a RhoA-dependent mechanism. Additionally, endogenous AT₂ receptors in preglomerular smooth muscle cells attenuate ANG II-mediated PLD activity. In the present study, we examined the signal transduction mechanisms used by endogenous AT₂ receptors to modulate ANG II-induced PLD activity through either PLA₂ generation of lysophosphatidylethanolamine or G_i-mediated generation of nitric oxide (NO) and interaction with RhoA. Blockade of AT₂ receptors, G_i and NO synthase, but not PLA₂, enhanced ANG II-mediated PLD activity in cells rich in, but not poor in, AT₂ receptors. Moreover, NO donors, a direct activator of guanylyl cyclase and a cGMP analog, but not lysophosphatidylethanolamine, inhibited ANG II-mediated PLD activity, whereas an inhibitor of guanylyl cyclase augmented ANG II-induced PLD activity. AT₂ receptor- and NO-mediated attenuation of ANG II-induced PLD activity was completely lost in cells transfected with S188A RhoA, which cannot be phosphorylated on serine 188. Therefore, our data indicate that AT₂ receptors activate G_i, subsequently stimulating NO synthase and leading to increased soluble guanylyl cyclase activity, generation of cGMP, and activation of a protein kinase, resulting in phosphorylation of RhoA on serine 188. Furthermore, because AT₂ receptors inhibit AT₁ receptor signaling to PLD via modulating RhoA activity, AT₂ receptor signaling can potentially regulate multiple vasoconstrictive signaling systems through inactivating RhoA.

cGMP; S188a RhoA; phosphorylation of RhoA; hypertension; vascular biology

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