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Pedroza, Albert J; Dalal, Alex R; Shad, Rohan; Yokoyama, Nobu; Nakamura, Ken; Mitchel, Olivia; Gilles, Casey; Hiesinger, William; Fischbein, Michael P
Arteriosclerosis, thrombosis, and vascular biology, 06/2023, Volume: 43, Issue: 6Journal Article
Smooth muscle cell (SMC) phenotypic reprogramming toward a mixed synthetic-proteolytic state is a central feature of aortic root aneurysm in Marfan syndrome (MFS). Previous work identified as a potential mediator of SMC plasticity in MFS. MFS ( ) mouse strains with an inducible vascular SMC fluorescent reporter ( ) with or without SMC-specific deletion of exons 2 to 3 ( ) were generated. Simultaneous SMC tracing and loss-of-function ( mice) was induced at 6 weeks of age. Aneurysm growth was assessed via serial echocardiography (4-24 weeks). Twenty-four-week-old mice were assessed via histology, RNA in situ hybridization, and aortic single-cell RNA sequencing. MFS mice demonstrated progressive aortic root dilatation compared with control (WT ) mice regardless of genotype ( <0.001), but there was no difference in aneurysm growth in versus ( =0.884). Efficient SMC deletion was confirmed via lineage-stratified genotyping, RNA in situ hybridization, and immunohistochemistry. Single-cell RNA sequencing of traced SMCs revealed a highly similar pattern of phenotype modulation marked by loss of contractile markers (eg, ) and heightened expression of matrix genes (eg, ) between genotypes. Pseudotemporal quantitation of SMC dedifferentiation confirmed that deletion did not alter the global extent of phenotype modulation, but reduced expression of 23 genes during this phenotype transition in mice, including multiple chondrogenic genes expressed by only the most severely dedifferentiated SMCs (eg, ). is not required to initiate SMC phenotype modulation in MFS aneurysm but may exert regulatory control over chondrogenic genes expressed in highly dedifferentiated SMCs.
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