A new role for the regulator of G-protein signalling-1 in inflammatory cell function in angiotensin ii-induced aortic aneurysm formation.

Chemokine-induced macrophage recruitment into the vascular wall is critical in the progression of atherosclerosis and aortic aneurysm formation. Macrophage activation and chemo-taxis can be mediated by chemokine ligation of multiple G-protein coupled receptors. The Regulator of G-Protein Signalling-1 (RGS1) acts to down-regulate the response to sustained chemokine stimulation. Studies in our laboratory have shown it to be up-regulated in ApoE-/- mice in association with atherosclerotic plaque progression and with monocyte-macro-phage activation; however an in vivo role for RGS1 in macrophage function has not been investigated. RGS1 has a non-redundant role in macrophage chemotaxis in vitro. Rgs1-/-ApoE-/-macrophages have significantly enhanced migratory responses to the chemokines CCL2, CCL3 and CCL5 (p<0.05) and have impaired desensitisation to repeated or sustained chemokine signalling, such that they show increased migration to CCL5 re-stimulation (p<0.001). RGS1 has a role in the accumulation of macrophages in lesions in the initial stages of atherosclerosis. In the absence of RGS1, atherosclerosis is attenuated in early lesions in the aortic root and aortas of female ApoE-/- mice (p<0.001). This was accompanied by reduced levels of macrophages in the aortic root. To investigate aortic leukocyte trafficking, an Angiotensin II model of acute vascular inflammation was used. At 9 weeks of age, Rgs1-/-ApoE-/- mice had significantly less CD45+ leukocytes and CD11b+ myeloid cells in aortas than ApoE-/- mice (p<0.05) after 5 days of Angiotensin II infusion. Notably, during a 2 week infusion, ApoE-/- mice were more susceptible to aortic aneurysm rupture in comparison to Rgs1-/-ApoE-/- mice with 56% survival vs. 94% (p=0.0147). Furthermore, between days 2 and 10, Angiotensin II treatment increased systolic blood pressure more in Rgs1-/-ApoE-/- mice than ApoE-/- mice (ApoE-/-117.4±4.0 mmHg vs. Rgs1-/-ApoE-/-137.7±3.1 mmHg) suggesting aneurysm formation in these mice is independent of Angiotensin-II induced hypertension. To examine the effects of Rgs1 disruption on vasomotility, myography studies were undertaken using the Gαq-coupled agonists; phenylephrine, angiotensin II and PGF2-α. Preliminary experiments showed only the contraction to phenylephrine was significantly enhanced in ApoE-/-rings compared to Rgs1-/-ApoE-/-(p<0.01) which may indicate a compensatory down regulation of α1-adrenergic receptors in Rgs1-/-ApoE-/- aortas. These findings identify a new role for RGS1 in inflammatory cell function and support a role for RGS1 in Angiotensin II induced-aneurysm formation. Furthermore, these data suggest a potential interaction between RGS1 and Gαq-coupled receptors that could account for the alterations in vascular contractile function and blood pressure observed in Rgs1-/-ApoE-/- mice. [ABSTRACT FROM AUTHOR]