Date Published: February 24, 2017
Publisher: Public Library of Science
Author(s): Zuzanna Rowinska, Thomas A. Koeppel, Maryam Sanati, Hubert Schelzig, Joachim Jankowski, Christian Weber, Alma Zernecke, Elisa A. Liehn, Marc W. Merx.
The CX3C chemokine receptor CX3CR1 is expressed on monocytes as well as tissue resident cells, such as smooth muscle cells (SMCs). Its role in atherosclerotic tissue remodeling of the aorta after transplantation has not been investigated.
We here have orthotopically transplanted infrarenal Cx3cr1-/-Apoe-/- and Cx3cr1+/+Apoe-/- aortic segments into Apoe-/-mice, as well as Apoe-/- aortic segments into Cx3cr1-/-Apoe-/- mice. The intimal plaque size and cellular plaque composition of the transplanted aortic segment were analyzed after four weeks of atherogenic diet.
Transplantation of Cx3cr-/-Apoe-/- aortic segments into Apoe-/- mice resulted in reduced atherosclerotic plaque formation compared to plaque size in Apoe-/- or Cx3cr1-/-Apoe-/- mice after transplantation of Apoe-/- aortas. This reduction in lesion formation was associated with reduced numbers of lesional SMCs but not macrophages within the transplanted Cx3cr-/-Apoe-/- aortic segment. No differences in frequencies of proliferating and apoptotic cells could be observed.
These results indicate that CX3CR1 on resident vessel wall cells plays a key role in atherosclerotic plaque formation in transplanted aortic grafts. Targeting of vascular CX3CL1/CX3CR1 may therefore be explored as a therapeutic option in vascular transplantation procedures.
Atherosclerosis is an inflammatory disease of the arteries with a high rate of morbidity and mortality in the Western World. The immune reactions involved in atherosclerotic plaque formation are controlled by lipid mediators, costimulatory molecules and cytokines. Chemokines are a family of chemotactic cytokines that mediate immune cell recruitment and are of high relevance in atherogenesis , and targeting of chemokines and their receptors has been shown to reduce experimental atherosclerosis [2–4].
Murine orthotopical transplantations of infrarenal aortic segments of Apoe-/- mice into Apoe-/- mice (control, n = 4), of Cx3cr1-/-Apoe-/- aortic segments into Apoe-/- mice (n = 5), as well as Apoe-/- aortic segments into Cx3cr1-/-Apoe-/- mice (n = 5) were performed using the sleeve technique [17,21], and mice were placed on atherogenic diet containing 21% fat and 0.15% cholesterol. Four weeks after transplantation, the aortic segments were harvested for further analysis.
We here employed a model of orthotopic transplantation of an infrarenal aortic segment into the infrarenal aorta of recicpient mice. Unlike in bone marrow transplantation models, which can be used to dissect the contribution of bone marrow versus non-bone marrow cells (including vessel wall cells but also all resident cells in other organs), this model allows to focus on the particular contribution of local (transferred) cells within the graft. Using this aorta transplantation model to discriminate between effects of circulating versus local vessel wall resident cells, we here are able to show that interference with the CX3CR1-driven signaling pathway in vessel wall cells inhibits atherosclerotic lesion formation.