Arteriolar and Venular Remodeling are Differentially Regulated by Bone Marrow‐Derived Cell‐Specific CX3CR1 and CCR2 Expression

Monocytes regulate microvascular remodeling (MR); however, the roles of different monocyte subpopulations in MR are largely unknown. Recent studies illustrate that CX3CR1 and CCR2 are key markers of inflammatory (CCR2 high /CX3CR1 low ) and resident (CCR2 low /CX3CR1 high ) monocytes. Using a model of MR in skin wound healing, we tested the hypothesis that bone marrow‐derived cell (BMC) CCR2 and CX3CR1 differentially regulate MR. Dorsal skin‐fold window chambers were implanted into wild‐type c57bl/6 (WT) mice and chimeric mice engrafted with either CCR2 −/− , CX3CR1 −/− , or WT (WT→WT, control) bone marrow resulting in differential knockout of CCR2 and CX3CR1 in BMCs only. WT→WT chimeric mice exhibited significant MR, with increases in maximum (under 10 −4 M adenosine vasodilation) arteriolar (59.6 ± 28.2%) and venular (29.1±11.5 %) diameters from day 7 to 14. In contrast, BMC‐specific CCR2 knockout completely abolished arteriolar (4.41±13.6%) remodeling but had an insignificant effect on venular (30.1±14.0%) remodeling. Knockout of BMC‐specific CX3CR1, however, partially attenuated both arteriolar (12.9±9.49%) and venular (9.06±5.97%) remodeling. WT window chamber tissue showed a significant increase in both the density and mass of CD45 + leukocytes from implantation to day 7, but no additional recruitment from day 7 to day 14. Further, the distribution of CX3CR1 and CCR2 positive BMCs in window chamber tissue did not change from day 7 to 14. Together, our data demonstrate that both CCR2 and CX3CR1 play critical, but differential, roles in MR in a skin wound healing response and that these roles likely influence cell recruitment during the first 7 days after injury. Therefore, targeting specific BMC subpopulations could differentially influence venular versus arteriolar MR. Supported by NIH HL74082 and AHA 10GRNT3490001.