Objective— Recent studies of bone marrow (BM)-transplanted apoE knockout (apoE^−/−) mice have concluded that a substantial fraction of smooth muscle cells (SMCs) in atherosclerosis arise from circulating progenitor cells of hematopoietic origin. This pathway, however, remains controversial. In the present study, we reexamined the origin of plaque SMCs in apoE^−/− mice by a series of BM transplantations and in a novel model of atherosclerosis induced in surgically transferred arterial segments.

Methods and Results— We analyzed plaques in lethally irradiated apoE^−/− mice reconstituted with sex-mismatched BM cells from eGFP⁺apoE^−/− mice, which ubiquitously express enhanced green fluorescent protein (eGFP), but did not find a single SMC of donor BM origin among ≈10 000 SMC profiles analyzed. We then transplanted arterial segments between eGFP⁺apoE^−/− and apoE^−/− mice (isotransplantation except for the eGFP transgene) and induced atherosclerosis focally within the graft by a recently invented collar technique. No eGFP⁺ SMCs were found in plaques that developed in apoE^−/− artery segments grafted into eGFP⁺apoE^−/− mice. Concordantly, 96% of SMCs were eGFP⁺ in plaques induced in eGFP⁺apoE^−/− artery segments grafted into apoE^−/− mice.

Conclusions— These experiments show that SMCs in atherosclerotic plaques are exclusively derived from the local vessel wall in apoE^−/− mice.