YIA5 RGS-1 Regulates Leukocyte Trafficking in Atherosclerosis and Aortic Aneurysm Formation through Chemokine Receptor Desensitisation.

: The regulation of macrophage recruitment and retention into the vascular wall is critical in the progression of atherosclerosis and aortic aneurysm formation. This can be mediated by chemokine activation of multiple G-protein coupled receptors. The Regulator of G-Protein Signalling-1 (RGS-1) acts to deactivate the intracellular response to sustained chemokine stimulation. We have found that RGS-1 is up-regulated with atherosclerotic plaque progression and with monocyte-macrophage activation. However little is known about the role of RGS-1 in macrophage function in vivo . Rgs-1 deficient macrophages have significantly enhanced migratory responses to atherogenic chemokines (p < 0.05) and have impaired desensitisation to repeated chemokine re-stimulation (p < 0.001). In vivo , RGS-1 has a role in the accumulation of macrophages in atherosclerotic lesions and during Angiotensin-II aortic aneurysm rupture. In the absence of RGS1, atherosclerosis is attenuated in early lesions in the aortic root and aortas of ApoE-/- mice (p < 0.001) which is accompanied by fewer macrophages in the aortic root. Rgs1-/-ApoE-/- mice are protected from Angiotensin-II induced aneurysm rupture compared to ApoE-/- mice with 94% survival vs. 56% (p = 0.0147). Rgs1-/-ApoE-/- mice have significantly fewer CD11b+ myeloid cells and CD14(+) macrophages in aortas than ApoE-/- mice (p < 0.05) after 5 days of Angiotensin-II infusion. Following bone marrow transplantation, recipient mice receiving ApoE-/- bone marrow were more susceptible to aortic aneurysm rupture (p = 0.0124), indicating bone marrow-derived RGS-1 is required for aneurysm rupture. Furthermore, Angiotensin-II treatment increased systolic blood pressure to a greater extent in Rgs1-/-ApoE-/- mice than ApoE-/- mice suggesting aneurysm formation in these mice is independent of Angiotensin-II induced hypertension and this is mediated by vascular-derived RGS-1.To gain insight into the mechanism by which RGS1 regulates trafficking, we selectively labelled inflammatory monocytes in vivo to track their movement into aortas following Angiotensin-II infusion. We found an accumulation of labelled CD45(+) cells in the aortas of ApoE-/- mice from day 3 to day 5 but not in Rgs1-/-ApoE-/- mice indicating RGS-1 as a regulator of macrophage retention in aortic aneurysms. These findings identify a novel role for RGS-1 in leukocyte function and vascular inflammation and identifies RGS-1 as a potential target for the treatment of cardiovascular disease.