Fibro-Cthrc1 fibroblasts, absent in normotensive aortas, drive aortic fibrosis in hypertensive mice and plasma CTHRC1 predicts hypertension risk in 24,000+ UK Biobank participants.
Identification of the Fibro-Cthrc1 fibroblast subcluster provides a novel mechanistic target for preventing aortic fibrosis and stiffening in hypertension.
Absolute Event Rate: 0% vs 0%
Abstract Background Aortic stiffening is a consequence of hypertension and a major contributor to end organ damage. A key driver of aortic stiffening is fibrosis involving the excess production of extracellular matrix (ECM) proteins such as collagen, fibronectin and laminin. Purpose The present study aimed to identify the cell types and signalling mechanisms that contribute to aortic fibrosis in hypertension. Methods and Results Male C57BL/6 mice (10–12-week-old) were randomly assigned to a 28-day angiotensin II (0.7 mg/kg/day) or vehicle (saline) infusion via osmotic minipump (s.c.). At endpoint, scRNA-seq analysis of 26,196 cells recovered all major aortic cell populations. Among these, fibroblasts exhibited the greatest heterogeneity and shift in gene expression after angiotensin II compared to all other cell types. Gene ontology (GO) analyses revealed that after angiotensin II treatment, a particular subcluster of fibroblasts (Fibro-Cthrc1) – characterised by its high expression of Cthrc1 – was especially fibrogenic. Fibro-Cthrc1 cells were nearly undetectable in aortas from vehicle-infused mice. Transcripts relating to ECM remodelling (Thbs2, Cdh11 and Postn) and collagen production (specifically collagen type I, III and V) were more highly enriched in Fibro-Cthrc1 compared to other fibroblasts within hypertensive aortas. Moreover, GO terms corresponding to profibrotic signalling pathways (i.e., cell adhesion, extracellular matrix organisation and collagen fibril organisation) were significantly enriched in Fibro-Cthrc1. Spatial transcriptomics and immunohistochemistry confirmed the presence of Fibro-Cthrc1 in the adventitial layer of angiotensin II-infused but not vehicle-infused mice. Finally, analysis of plasma analytes in approximately 24,000 participants of the UK Biobank collection revealed CTHRC1 to be strongly associated with raised systolic blood pressure and pulse pressure, and a strong predictor of the risk of developing hypertension over a 15-year follow-up. Conclusion Our study identifies a novel fibroblast subcluster, Fibro-Cthrc1, as a potential driver of aortic fibrosis and stiffening in hypertension. This cluster is absent in normotensive aortas, suggesting that targeting Fibro-Cthrc1 therapeutically could prevent aortic fibrosis and its associated hypertensive end-organ damage. Notably, such an approach may avoid compromising physiological extracellular matrix production and vessel integrity.
Drummond et al. (Sat,) reported a other. Fibro-Cthrc1 fibroblasts, absent in normotensive aortas, drive aortic fibrosis in hypertensive mice and plasma CTHRC1 predicts hypertension risk in 24,000+ UK Biobank participants.