Endothelial Protective Monocyte Patrolling in Large Arteries Intensified by Western Diet and Atherosclerosis
Rationale: Non-classical mouse monocyte (CX3CR1high, Ly-6Clow) patrolling along the vessels of the microcirculation is critical for endothelial homeostasis and inflammation. Due to technical challenges it is currently not established how patrolling occurs in large arteries.
Objective: This study was undertaken to elucidate the molecular, migratory and functional phenotype of patrolling monocytes in the high shear and pulsatile environment of large arteries in healthy, hyperlipidemic and atherosclerotic conditions.
Methods and Results: Applying a new method for stable, long-term two-photon intravital microscopy of unrestrained large arteries in live CX3CR1-GFP mice, we show that non-classical monocytes patrol inside healthy carotid arteries at a velocity of 36 μm/min, three times faster than in microvessels. The tracks are less straight but lead preferentially downstream. The number of patrolling monocytes is increased 9-fold by feeding wildtype mice a western diet or by applying topical TLR7/8 agonists. A similar increase is seen in CX3CR1+/GFP/apoE-/- mice on chow diet, with a further 2-3-fold increase on western diet (22-fold over healthy). In plaque conditions, monocytes are readily captured onto the endothelium from free flow. Stable patrolling is unaffected in CX3CR1-deficient mice and involves the contribution of LFA-1 and α4 integrins. The endothelial damage in atherosclerotic carotid arteries was assessed by electron microscopy and correlates with the number of intraluminal patrollers. Abolishing patrolling monocytes in Nr4a1-/- apoE-/- mice leads to pronounced endothelial apoptosis.
Conclusions: Arterial patrolling is a prominent new feature of non-classical monocytes with unique molecular and kinetic properties. It is highly upregulated in hyperlipidemia and atherosclerosis in an CX3CR1-independent fashion, and plays a potential role in endothelial protection.
- Received January 31, 2017.
- Revision received March 14, 2017.
- Accepted March 16, 2017.
Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDervis License (http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made.