(a) Experimental outline for b-h. Leprfl/fl mice and Prrx1-creERT2:Leprfl/fl littermates were injected with tamoxifen and received a single IV injection of AAV-PCSK9 followed by a high fat diet for 12 weeks. (b) Representative cross sections of aortic roots stained with Oil red O and assessment of lesion size (*p = 0.042, n = 8 animals per group, two-tailed Student’s t-test). (c) Flow cytometry enumeration of myeloid cells in aortas of Leprfl/fl and Prrx1-creERT2:Leprfl/fl mice (*p = 0.023, n = 8 animals per group, two-tailed Student’s t-test). (d) CD68 histological staining of aortic root lesions. Percentage of positive staining per plaque (*p = 0.029, n = 6 animals for Leprfl/fl, n = 8 for Prrx1-creERT2:Leprfl/fl, two-tailed U test). (e) Representative flow plots and statistical analysis of long-term hematopoietic stem cells (LT-HSC) in femur bone marrow (*p = 0.046, n = 9 animals per group, two-tailed Student’s t-test). (f) Bone marrow unit assay for complete colonies (CFU-C) of bone marrow mononuclear cells (BMNCs) (*p = 0.036, n = 9 animals per group, two-tailed Student’s t-test). (g) BrdU incorporation assay 22 hours after intraperitoneal injection for LT-HSC and progenitors (GMP) proliferation (*p = 0.027 for LT-HSC, *p = 0.017 for GMP, n = 9 animals per group, two-tailed Student’s t-test). (h) Circulating myeloid cells at Zeitgeber time 7 (*p = 0.014 for neutrophils, *p = 0.046 for monocytes, n = 10 animals for Leprfl/fl, n = 9 for Prrx1-creERT2:Leprfl/fl, two-tailed Student’s t-test). Data are mean ± s.e.m. (i) Athero-express cohort. The illustrates inclusion criteria for patients and separation into sedentary lifestyle and exercise groups. We acknowledge Servier Medical Art (https://smart.servier.com) for providing images of mice and components of the cartoon.