Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice

Abstract

The authors wish to add the following information. Table 1: The doses of antagonists used to treat wild-type and RGS2-knockout mice were hexamethonium at 5 mg/kg i.v., prazosin at 200 µg/kg i.v., and candesartan at 100 µg/kg i.v. Effective ganglionic blockade by hexamethonium was established as described previously, whereas blockade by prazosin or candesartan was demonstrated by the inability of a subsequent infusion of phenylephrine (10 µg/kg i.v.) or angiotensin II (1 µg/kg i.v.) to increase blood pressure of wild-type or RGS2-knockout mice. Figure 3:Blood pressure responses were determined using anesthetized mice as described in Methods. In Figure 3a, the doses of vasoconstrictors used to treat wild-type and RGS2-knockout mice were 1 µg/kg i.v. for angiotensin II and 10 µg/kg i.v. for phenylephrine. These doses were determined empirically, as were those that elicited a near-maximal (>75%) increase in blood pressure (determined by dose-response experiments such as those shown in Figure 4a for phenylephrine). In Figure 3b, candesartan (100 µg/kg i.v.) was infused into wild-type and RGS2-knockout mice over a period of 10 seconds, after which blood pressure was recorded continuously over the time period indicated. In Figure 3c, the same dose of angiotensin II (1 µg/kg iv) was used to treat wild-type and RGS2-knockout mice in order to increase systolic blood pressure to similar absolute levels (160-170 mmHg) prior to antagonist infusion (candesartan, 100 µg/kg i.v.). This approach was established by the results shown in Figure 3a, in which MAP of wild-type mice increased from a resting value (prior to agonist infusion) of ∼85 mmHg to a value of ∼135 mmHg after angiotensin II infusion, and the MAP of RGS2-knockout mice increased from a resting value of ∼135 mmHg to ∼140 mmHg by the same treatment. After a maximal effect of angiotensin II on blood pressure was achieved (∼1 minute), candesartan (100 µg/kg i.v.) was infused over 10 seconds, and decreases in blood pressure were recorded continuously over the time period indicated.

Regulators of G‐protein signalling are modulated by bacterial lipopeptides and lipopolysaccharide

“…The effect on RGS modulation resembles the results we obtained after poly(I:C) stimulation, thus proving the responsibility of the TRIF activation for the upregulation of both RGS mRNA. Stimulation of TLR3 and activation of the TRIF pathway leads to interferon-b production [35]. Takaoka et al [36] demonstrated that interferon-b can induce the transcription of p53 and this is critical for an antiviral defence of the host.…”

Hypertension‐evoked RhoA activity in vascular smooth muscle cells requires RGS5

“…Of interest, genes that encode RGS proteins 2, 4, and 5 are clustered on a locus of chromosome 1 that has been associated with the development of hypertension in different ethnic groups (13). In line with this, the genetic ablation of RGS2 in mice causes hypertension (14), whereas loss of RGS5-a potent inhibitor of Ga q/11 and Ga i/o activityresults in hypotensive (15), normotensive (16), and hypertensive (17,18) animals, depending on their genetic background. As can be deduced from these divergent results, the functional role of RGS5 in the regulation of blood pressure, the VSMC phenotype, and arterial remodeling seem to be context dependent and are still debated.…”

Origin‐specific epigenetic program correlates with vascular bed‐specific differences inRgs5expression

“…Previous studies described phenotypic differences in VSMCs derived from CNC-and mesenchyme-derived VSMCs (5). Data from our group and others suggested that RGS proteins are important regulators of G-protein signaling in VSMCs (12,27). Accordingly, we here used real-time RT-PCR to determine whether differences in RGS isoform expression in the common carotid artery (CNC derived) and descending (abdominal) aorta (mesenchyme derived) may contribute to known phenotypic differences in VSMCs from different developmental origins ( Fig.…”