Lin et al., Arterioscler Thromb Vasc Biol, 2021

Arterioscler Thromb Vasc Biol. 2021 Sep 30: ATVBAHA120315681; doi: 10.1161/ATVBAHA.120.315681. Online ahead of print.

Vascular Smooth Muscle Cell Subpopulations and Neointimal Formation in Mouse Models of Elastin Insufficiency

Chien-Jung Lin, Bridget Hunkins, Robyn Roth, Chieh-Yu Lin, Jessica E Wagenseil, Robert P Mecham

 

Abstract
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.

Editorial in

Arterioscler Thromb Vasc Biol. 2021 Oct 28;ATVBAHA121317021; doi:10.1161/ATVBAHA.121.317021. Online ahead of print.

Aortic Neointimal Formation: The Role of Elastin in Conjunction with Vascular Smooth Muscle Cell Origin

Kimberly R Rebello, Scott A LeMaire, Ying H Shen