Abstract 1354: Interferon-Beta Signaling Regulates Arteriogenesis Through its Effects on Monocyte Apoptosis and Smooth Muscle Cell Proliferation
Purpose: Circulating monocytes orchestrate collateral artery growth (arteriogenesis). In a recent study, we demonstrated that monocytes from patients with insufficient coronary collateral artery growth show increased expression of the interferon(IFN)-beta pathway compared to patients with adequate arteriogenesis. Here, we investigated the underlying mechanisms of the effect of modulation of IFNbeta-signaling on arteriogenesis.
Methods and Results: Collateral dependent hindlimb perfusion was assessed one week after femoral artery ligation in control, IFNbeta treated and IFNalpha/beta-receptor knockout (IFNAR−/−) mice by infusing fluorescent microspheres under conditions of maximal vasodilation. IFN-beta treatment significantly reduced perfusion restoration compared to PBS-treated control mice, expressed as percentage ligated/non-ligated hindlimb (31.5±4.1% vs. 41.9±8.2%, p=0.01), while mice lacking the IFNbeta-receptor showed significantly increased hindlimb perfusion (54.3±6.6%, p<0.001 vs. control). Immunohistochemistry showed IFNAR predominantly in the vascular media. Expression of genes of the IFNbeta-pathway (IFNbeta, STAT1, CXCL10, CXCL11) was reduced in stimulated monocytes and hindlimb tissue from IFNAR−/− mice. Pro-apoptotic TRAIL was significantly enhanced in IFNbeta treated animals and increased in vascular smooth muscle cells (SMCs) in-vitro upon stimulation with IFNbeta. In-vitro, IFN-beta dose-dependently enhanced apoptosis of THP1-monocytes, inhibited proliferation of SMCs, and upregulated cyclin-dependent kinase inhibitors p21, but not p15 or p27 in SMCs. IFNbeta downstream cytokines CXCL10 and IL15 did not have an effect on SMC proliferation. Inhibition of IFNbeta signaling in-vitro by transfection of SMCs with siRNA against IFNAR stimulated SMC proliferation. Attenuated IFNbeta signaling led to a downregulation of p21 expression in SMCs.
Conclusion: IFNbeta attenuates collateral artery growth by inducing monocyte apoptosis and directly inhibiting SMC proliferation via an upregulation of the cell-cycle regulator p21. Blockade of IFNbeta-signaling enhances arteriogenesis in-vivo, probably through increased SMC proliferation due to an attenuation of p21 expression.