Expression of Human Tissue Factor Pathway Inhibitor on Vascular Smooth Muscle Cells Inhibits Secretion of Macrophage Migration Inhibitory Factor and Attenuates Atherosclerosis in ApoE-/- Mice
Background—Tissue factor (TF) and coagulation proteases are involved in promoting atherosclerosis, but the molecular and cellular basis for their involvement is unknown.
Methods and Results—We generated a new strain (ApX4) of ApoE-deficient mice expressing a membrane-tethered human tissue factor pathway inhibitor (TFPI) fusion protein on smooth muscle actin positive cells, including vascular smooth muscle cells (SMC). ApX4 mice developed little atherosclerosis, on either normal Chow or high fat diets. Lipid levels were similar to those in parental ApoE-/- mice and there was no detectable difference in systemic (circulating) TFPI levels or activity. The small lipid-rich lesions that developed had markedly reduced leukocyte infiltrates and, in contrast to ApoE-/- mice, SMC did not express macrophage migratory inhibitory factor (MIF), including at sites distant from atheromatous lesions. Low levels of circulating MIF in ApX4 mice normalised to levels seen in ApoE-/- mice after injection of an inhibitory anti-hTFPI antibody, which also led to MIF expression by TF-positive medial SMC. MIF production by SMC in ApoE-/- mice in vitro and in vivo was shown to be dependent on TF and PAR signalling, which were inhibited in ApX4 mice.
Conclusions—Our data indicate that TF plays a hitherto unreported role in the generation of MIF by SMC in atherosclerosis-prone ApoE-/- mice, inhibition of which significantly prevents the development of atherosclerosis, through inhibition of leukocyte recruitment. These data significantly enhance our understanding of the pathophysiology of this important pathology and suggest new potential translational strategies to prevent atheroma formation.
- Received September 23, 2014.
- Revision received January 10, 2015.
- Accepted February 6, 2015.