Abstract 18625: Mechano-Transcriptomic Interaction Mediates Spatial Variations in Early Vascular Fibrosis

Abstract

Background: The spatiotemporal variations of wall shear stress (WSS) modulate vascular genomics and function. Despite the advances in imaging modalities and computational modeling, the link between local hemodynamics and genetic pathways underlying atherosclerosis development remains elusive. We hypothesized that differential WSS patterns in the aorta modulate fibroblast gene expression in response to high fat diet (HFD) leading to vascular stiffness. Methods: We performed ultrasound-based 4-D+time moving boundary computational fluid dynamics (CFD) on the aorta of Ldlr -/- mice fed a normal diet (ND) or HFD during 4 weeks. B-mode images (Vevo 3100) of the aortic arch were used to reconstruct a 3-D model of the lumen structure by revolving the vessel wall around the centerline in the aorta and the branches. Computational domain reconstruction was followed by image registration to generate a moving boundary model. WSS contours and velocity profiles were acquired by solving Navier-Stokes equations using svFSI code. The longitudinal strains along the outer curvature of the aortic arch over several cardiac cycles were measured, and the changes were compared with the effects of HFD. Mouse aortas were processed for single cell RNA sequencing and analyzed using the Scanpy package. Results and Conclusion: Our analysis of transcriptomics profiles revealed increased Acta2 and Postn expression in the myofibroblast subclusters, suggesting myofibroblast differentiation in response to HFD in the aortic arch. This was confirmed and localized to the lesser curvature of the aortic arch through Periostin immunostaining. We found that the increase in Postn and Acta2 is associated with reduced arterial strain or increased arterial stiffness measured in the aortic arch. In parallel, CFD analysis demonstrated that an elevated WSS along the outer curvature vs. low WSS and disturbed flow along the inner curvature in early diastole results in differential gene expression to regulate myofibroblast differentiation and modulates vascular stiffness.