023P Brighton
Winter Meeting December 2007



The inflammatory chemokine MIP-1β, a ligand for the HIV co-receptor CCR5, is a potent vasoconstrictor of human blood vessels in vitro: antagonism by maraviroc


Janet Maguire1, Rhoda Kuc1, Sidath Katugampola2, Katie Jones1, Roy Mansfield2, Carolyn Napier2, Anthony Davenport1
1University of Cambridge, Cambridge, United Kingdom, 2Pfizer Global Research and Development, Sandwich, Kent, United Kingdom


The chemokine receptor CCR5 is a major co-receptor for the HIV virus. Interestingly, HIV-infected individuals are at increased risk of cardiovascular events, possibly owing to accelerated atherosclerosis and CCR5 deficiency results in a reduction in diet-induced atherosclerosis in ApoE-/ mice (Braunersreuther et al., 2007). Both CCR5 and its selective, endogenous ligand MIP-1β are expressed in human cultured vascular smooth muscle (Schecter et al., 2000). However, a direct effect on vascular tone of chemokines has not been reported in human blood vessels that are susceptible to atherosclerosis. Human saphenous vein (SV) is a widely used graft in patients with coronary artery disease and grafts, particularly SV, exhibit an accelerated form of atherosclerosis. This makes the SV a useful model system of disease. We have determined whether MIP1-β has direct constrictor or dilator action in SV and confirmed that this is a CCR5 mediated action using the selective antagonist maraviroc (UK-427,857; Dorr et al., 2005).




Human SV, obtained with ethical approval, were cut into 4mm rings, mechanically denuded of their endothelium and mounted in 5ml organ baths, containing Krebs’ solution at 37°C, for isometric tension recording. Following normalisation to optimise basal resting tension, removal of the endothelium was confirmed in veins pre-constricted with phenylephrine by the absence of vasodilatation to ACh. Cumulative concentration-response curves (CRC) were then constructed to MIP-1β (10-11-1.1x10-7M). In adjacent rings of SV from some patients, 300nM maraviroc or vehicle (DMSO 0.01%) was added to the bathing medium and cumulative CRC to MIP-1β constructed 30 minutes later. In additional experiments, CRC to MIP-1β were constructed in SV that had been preconstricted with endothelin-1 (10nM) and experiments terminated by addition of 30μM SNAP. Vasoconstrictor responses were expressed as a %phenylephrine and vasodilator responses as %reversal of ET-1 constriction. Data were analysed using FigSys (Biosoft, Cambridge, UK) to determine values of pD2 and maximum response. n-Values are the number of patients from whom tissue was obtained.

MIP-1β did not elicit direct vascular smooth muscle relaxation in ET-1 constricted SV, over the concentration range tested. In contrast MIP-1β produced a concentration-dependent contraction of SV with pD2 of 7.70±0.16 (n=12). In the presence of 300nM maraviroc (n=4), the constrictor response to MIP1-β was abolished (Fig 1).

We have discovered an as yet unidentified role for the chemokine MIP-1β as a potent constrictor of human SV, an effect mediated through the CCR5 receptor present on vascular smooth muscle.



Braunersreuther V et al. (2007). Arterioscler Thromb Vasc Biol 27, 373-379.

Dorr P et al. (2005). Antimicrob Agents Chemother 49, 4721-4732.

Schecter AD et al. (2000). J Biol Chem 275, 5466-5471.