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Smooth muscle cell specific deletion of the PKGIα target RGS2 induces vascular dysfunction and hypertension

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HAL Id: inserm-00663626

https://www.hal.inserm.fr/inserm-00663626

Submitted on 27 Jan 2012

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Smooth muscle cell specific deletion of the PKGIα target

RGS2 induces vascular dysfunction and hypertension

Robrecht Thoonen, Haihua Zhang, Yuichi Abe, Heather Nickerson, Mark

Aronovitz, Pierre Chambon, Richard Karas, Michael Mendelsohn

To cite this version:

Robrecht Thoonen, Haihua Zhang, Yuichi Abe, Heather Nickerson, Mark Aronovitz, et al.. Smooth

muscle cell specific deletion of the PKGIα target RGS2 induces vascular dysfunction and hypertension.

5th International Conference on cGMP: Generators, Effectors and Therapeutic Implications, Jun 2011,

Halle, Germany. pp.P72, �10.1186/1471-2210-11-S1-P72�. �inserm-00663626�

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P O S T E R P R E S E N T A T I O N

Open Access

Smooth muscle cell specific deletion of the PKGI

a

target RGS2 induces vascular dysfunction and

hypertension

Robrecht Thoonen

1*

, Haihua Zhang

1

, Yuichi Abe

1

, Heather Nickerson

1

, Mark Aronovitz

1

, Pierre Chambon

2

,

Richard H Karas

1

, Michael E Mendelsohn

1,3

From 5th International Conference on cGMP: Generators, Effectors and Therapeutic Implications

Halle, Germany. 24-26 June 2011

Introduction

Current dogma regarding the etiology of hypertension states that renal abnormalities of sodium handling cause an increase in blood volume that overwhelms vascular counter-regulatory responses, resulting in hypertension. Although it is known that acute changes in vascular mor-phology and tone can cause an increase in vascular resis-tance and blood pressure, we have hypothesized that primary abnormalities of the regulation of vascular smooth muscle tone can also be an etiology for hyperten-sion. We have previously demonstrated that disruption of the leucine zipper targeting domain in PKGIa results in dysregulation of vasomotor tone and hypertension in the setting of normal renal function. To directly test the hypothesis that abnormalities in vasomotor regulation can be the primary etiology of hypertension, we have developed and now characterize a novel mouse model harboring a smooth muscle cell (SMC) specific deletion of the PKGIa target we identified previously, RGS2, a GTPase activating protein that inhibits Gq-coupled G-protein coupled receptor (GPCR) signaling, whose total body deletion in mice causes hypertension (Tang et al, Nature Medicine, 2003).

Results

Smooth muscle specific RGS2 knockout mice (RGS2-SMC-KO) were generated by crossing mice carrying an RGS2 gene with exons 2 to 5 flanked by LoxP sites with inducible SMA-CRE-ERT2mice. SMC-specific deletion of RGS2 was induced by tamoxifen administration at the

age of 7 weeks. Cre negative mice treated with tamoxifen were used as controls. Telemetric monitoring (DSI) of blood pressure (BP) and heart rate (HR) in male RGS2-SMC-KO mice showed that these mice have a significant increase in systolic BP vs. control mice (135 ± 5 mmHg vs. 122 ± 7 mmHg, respectively.P<0.01) without a conco-mitant change in HR. The change in BP after challenge with a bolus injection of the NOS inhibitor L-NAME (50 mg/kg i.v.) was significantly less in the RGS2-SMC-KO mice compared to WT mice. (ΔSBP: 38 ± 7 mmHg vs. 47 ± 3 mmHg, respectively.P<0.001), consistent with decreased basal endogenous NO signaling. BP responses to changes in dietary sodium intake in the RGS2-SMC-KO mice were identical to control mice.

Conclusion

Though further characterization of renal function and vasomotor regulation in RGS2-SMC-KO mice is ongoing, the current data demonstrate the presence of hyperten-sion in these mice, together with normal sodium hand-ling, supporting the hypothesis that high blood pressure can arise from a primary abnormality of vascular smooth muscle cell contractile regulation. These findings, taken together with the diminished SBP response to L-NAME, support that endogenous NO signaling, and the activa-tion of the NO-sGC-PKGI pathway in smooth muscle cells, are necessary to maintain normal vascular tone and blood pressure by attenuating Gq mediated GPCR con-strictive signaling.

Author details

1

Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA.2IGBMC, CNRS/INSERM/ULP, Collège de France, Illkirch

* Correspondence: rthoonen@tuftsmedicalcenter.org

1

Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA

Full list of author information is available at the end of the article Thoonen et al. BMC Pharmacology 2011, 11(Suppl 1):P72 http://www.biomedcentral.com/1471-2210/11/S1/P72

© 2011 Thoonen et al; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Cedex, France.3Present address, Merck Research Laboratories, Rahway, NJ,

USA.

Published: 1 August 2011

doi:10.1186/1471-2210-11-S1-P72

Cite this article as: Thoonen et al.: Smooth muscle cell specific deletion of the PKGIa target RGS2 induces vascular dysfunction and

hypertension. BMC Pharmacology 2011 11(Suppl 1):P72.

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Thoonen et al. BMC Pharmacology 2011, 11(Suppl 1):P72 http://www.biomedcentral.com/1471-2210/11/S1/P72

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