Journal
CARDIOVASCULAR RESEARCH
Volume 94, Issue 3, Pages 545-554Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvs126
Keywords
Atherosclerosis; Circulating progenitors; Osteochondrogenic differentiation; Smooth muscle cells; Vascular calcification
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Funding
- NIH [R01 HL081785, R01 HL62329, R01 HL080597, K01 DK075665]
- New Investigator Award [P30 DK017047]
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Vascular cartilaginous metaplasia and calcification are common in patients with atherosclerosis. However, sources of cells contributing to the development of this complication are currently unknown. In this study, we ascertained the origin of cells that give rise to cartilaginous and bony elements in atherosclerotic vessels. We utilized genetic fate mapping strategies to trace cells of smooth muscle (SM) origin via SM22-Cre recombinase and Rosa26-LacZ Cre reporter alleles. In animals expressing both transgenes, co-existence within a single cell of -galactosidase [marking cells originally derived from SM cells (SMCs)] with osteochondrogenic (Runx2/Cbfa1) or chondrocytic (Sox9, type II collagen) markers, along with simultaneous loss of SM lineage proteins, provides a strong evidence supporting reprogramming of SMCs towards osteochondrogenic or chondrocytic differentiation. Using this technique, we found that vascular SMCs accounted for approximate to 80 of Runx2/Cbfa1-positive cells and almost all of type II collagen-positive cells (approximate to 98) in atherosclerotic vessels of LDLr/ and ApoE/ mice. We also assessed contribution from bone marrow (BM)-derived cells via analysing vessels dissected from chimerical ApoE/ mice transplanted with green fluorescence protein-expressing BM. Marrow-derived cells were found to account for approximate to 20 of Runx2/Cbfa1-positive cells in calcified atherosclerotic vessels of ApoE/ mice. Our results are the first to definitively identify cell sources attributable to atherosclerotic intimal calcification. SMCs were found to be a major contributor that reprogrammed its lineage towards osteochondrogenesis. Marrow-derived cells from the circulation also contributed significantly to the early osteochondrogenic differentiation in atherosclerotic vessels.
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