TY - JOUR
T1 - Vascular Smooth Muscle Cell Subpopulations and Neointimal Formation in Mouse Models of Elastin Insufficiency
AU - Lin, Chien Jung
AU - Hunkins, Bridget M.
AU - Roth, Robyn A.
AU - Lin, Chieh-Yu
AU - Wagenseil, Jessica E.
AU - Mecham, Robert P.
N1 - Funding Information:
This study was partially funded by National Science Foundation grant 1662434 (J.E. Wagenseil) and National Institutes of Health grants R56 HL152420 (J.E. Wagenseil) and HL-53325 (R.P. Mecham). C.-J. Lin was supported by T32HL007081 and T32HL125241. The Ines Mandl Research Foundation also provided funds to R.P. Mecham.
Funding Information:
This study was partially funded by National Science Foundation grant 1662434 (J.E. Wagenseil) and National Institutes of Health grants R56 HL152420 (J.E. Wagenseil) and HL-53325 (R.P. Mecham). C.-J. Lin was supported by T32HL007081 and T32HL125241. The Ines Mandl Research Foundation also provided funds to R.P. Mecham.
Publisher Copyright:
© 2021 American Heart Association, Inc.
PY - 2021/12/1
Y1 - 2021/12/1
N2 - OBJECTIVE: Using a mouse model of Eln (elastin) insufficiency that spontaneously develops neointima in the ascending aorta, we sought to understand the origin and phenotypic heterogeneity of smooth muscle cells (SMCs) contributing to intimal hyperplasia. We were also interested in exploring how vascular cells adapt to the absence of Eln. APPROACH AND RESULTS: We used single-cell sequencing together with lineage-specific cell labeling to identify neointimal cell populations in a noninjury, genetic model of neointimal formation. Inactivating Eln production in vascular SMCs results in rapid intimal hyperplasia around breaks in the ascending aorta’s internal elastic lamina. Using lineage-specific Cre drivers to both lineage mark and inactivate Eln expression in the secondary heart field and neural crest aortic SMCs, we found that cells with a secondary heart field lineage are significant contributors to neointima formation. We also identified a small population of secondary heart field-derived SMCs underneath and adjacent to the internal elastic lamina. Within the neointima of SMC-Eln knockout mice, 2 unique SMC populations were identified that are transcriptionally different from other SMCs. While these cells had a distinct gene signature, they expressed several genes identified in other studies of neointimal lesions, suggesting that some mechanisms underlying neointima formation in Eln insufficiency are shared with adult vessel injury models. CONCLUSIONS: These results highlight the unique developmental origin and transcriptional signature of cells contributing to neointima in the ascending aorta. Our findings also show that the absence of Eln, or changes in elastic fiber integrity, influences the SMC biological niche in ways that lead to altered cell phenotypes.
AB - OBJECTIVE: Using a mouse model of Eln (elastin) insufficiency that spontaneously develops neointima in the ascending aorta, we sought to understand the origin and phenotypic heterogeneity of smooth muscle cells (SMCs) contributing to intimal hyperplasia. We were also interested in exploring how vascular cells adapt to the absence of Eln. APPROACH AND RESULTS: We used single-cell sequencing together with lineage-specific cell labeling to identify neointimal cell populations in a noninjury, genetic model of neointimal formation. Inactivating Eln production in vascular SMCs results in rapid intimal hyperplasia around breaks in the ascending aorta’s internal elastic lamina. Using lineage-specific Cre drivers to both lineage mark and inactivate Eln expression in the secondary heart field and neural crest aortic SMCs, we found that cells with a secondary heart field lineage are significant contributors to neointima formation. We also identified a small population of secondary heart field-derived SMCs underneath and adjacent to the internal elastic lamina. Within the neointima of SMC-Eln knockout mice, 2 unique SMC populations were identified that are transcriptionally different from other SMCs. While these cells had a distinct gene signature, they expressed several genes identified in other studies of neointimal lesions, suggesting that some mechanisms underlying neointima formation in Eln insufficiency are shared with adult vessel injury models. CONCLUSIONS: These results highlight the unique developmental origin and transcriptional signature of cells contributing to neointima in the ascending aorta. Our findings also show that the absence of Eln, or changes in elastic fiber integrity, influences the SMC biological niche in ways that lead to altered cell phenotypes.
KW - cell differentiation
KW - elastin
KW - extracellular matrix
KW - myocytes
KW - neointima
KW - smooth muscle
UR - http://www.scopus.com/inward/record.url?scp=85120435515&partnerID=8YFLogxK
U2 - 10.1161/ATVBAHA.120.315681
DO - 10.1161/ATVBAHA.120.315681
M3 - Article
C2 - 34587758
AN - SCOPUS:85120435515
SN - 1079-5642
VL - 41
SP - 2890
EP - 2905
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 12
ER -