Abstract Tu0014: Single cell RNA sequencing reveals adaptive and maladaptive transcriptional signature across aortic cell types in a mouse model of Autosomal Recessive Cutis Laxa type 1B

Le résumé fourni par la source

Thoracic aorta aneurysms (TTA) are localized dilations that predispose the aorta to dissection or rupture. Autosomal Recessive Cutis Laxa type 1B (ARCL1B) is a connective tissue disorder caused by homozygous loss of function mutations in the EFEMP2/FBLN4 gene. This disorder is associated with increased risk of aneurysms, including in the ascending aorta. To better understand the mechanisms that predispose the ascending aorta to medial weakening and dilation, we performed single-cell RNA sequencing of the aorta of the Fbln4 E57K/E57K mouse model, which carries homozygous loss-of-function mutations analogous to those found in ARCL1B patients. We found that, when dilation is relatively modest (~10-weeks of age), vascular smooth muscle cells (VSMC) from the aorta of Fbln4 E57K/E57K mice upregulated expression of “adaptive” transcripts and pathways relative to controls, including expression of Lox , Lox1, Eln, and Fn1 , possibly compensating, in part, for fibulin-4 deficiency. However, Fbln4 E57K/E57K VSMCs also up-regulated expression of the transcript coding for Angiotensin Converting Enzyme ( Ace) , a factor known to worsen vascular pathogenesis in related conditions. Ace upregulation was most notable in a small VSMC cluster that was exclusively present in the Fbln4 E57K/E57K aorta, and which was also characterized by a transcriptional profile suggestive of cell stress and matrix-degradation, similar to that observed in VSMCs derived from severely dilated aortas of Loeys-Dietz syndrome (LDS) mouse models. We also noted that endothelial cells (EC) from Fbln4 E57K/E57K aortas (but not LDS aorta) expressed a transcriptional profile characteristic of ECs exposed to “perturbed flow”, including reduced expression of Piezo1 , which encodes for Piezo Type Mechanosensitive Ion Channel Component 1. We hypothesize that perturbed mechanosensitive processes in Fbln4 E57K/E57K ECs may contribute to expansion of the “pathogenic” VSMC clusters and/or exacerbation of maladaptive transcriptional profiles in neighboring VSMCs, possibly by enhancement of Angiotensin II signaling. We are currently assessing how these pathways are altered in TAA of varying severity, and functionally assessing their role in pathogenesis.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.