Identification of intima-to-media signals for flow-induced vascular remodeling using correlative gene expression analysis

Changes in blood flow can induce arterial remodeling. Intimal cells sense flow and send signals to the media to initiate remodeling. However, the nature of such intima-media signaling is not fully understood. To identify potential signals, New Zealand white rabbits underwent bilateral carotid ligation to increase flow in the basilar artery or sham surgery (n = 2 ligated, n = 2 sham). Flow was measured by transcranial Doppler ultrasonography, vessel geometry was determined by 3D angiography, and hemodynamics were quantified by computational fluid dynamics. 24 h post-surgery, the basilar artery and terminus were embedded for sectioning. Intima and media were separately microdissected from the sections, and whole transcriptomes were obtained by RNA-seq. Correlation analysis of expression across all possible intima-media gene pairs revealed potential remodeling signals. Carotid ligation increased flow in the basilar artery and terminus and caused differential expression of 194 intimal genes and 529 medial genes. 29,777 intima-media gene pairs exhibited correlated expression. 18 intimal genes had > 200 medial correlates and coded for extracellular products. Gene ontology of the medial correlates showed enrichment of organonitrogen metabolism, leukocyte activation/immune response, and secretion/exocytosis processes. This demonstrates correlative expression analysis of intimal and medial genes can reveal novel signals that may regulate flow-induced arterial remodeling.