Chronic 3D Vascular-Immune Interface Established by Coculturing Pressurized Resistance Arteries and Immune Cells

Abstract

Chronic exposure of the arterial vasculature to high blood pressure recruits immune cells and contributes to the vascular remodeling, dysfunction, and inflammation observed in hypertension. The mechanisms underlying the interaction between vascular and immune cells remain unknown, hampering the development of effective therapies targeting the vascular-immune interface. Overcoming these limitations requires a reliable, physiologically relevant experimental model of vascular-immune interface. By coculturing a 3-dimensional organ culture vascular system with immune cells of interest, we reproduced ex vivo the vascular-immune interface that occurs in hypertension. In the 3-dimensional vascular-immune interface model, CD8 but not CD4 T cells isolated from hypertensive mice increased the contractile properties of resistance arteries in naive mice, indicating that CD8 lymphocytes directly contribute to enhanced peripheral resistance in hypertension. RNA sequencing of CD8 lymphocytes isolated from prehypertensive mice revealed upregulation of gene pathways involved in chemotaxis, response to IFN-γ and other external stimuli, MAPK cascade activation, and positive regulation of intracellular calcium fluxes, as compared with CD4 T cells. Taken together, these results indicate that hypertensive stimuli program CD8 T cells toward a phenotype with promigratory properties that might account for their ability to enhance myogenic tone of resistance arteries when cocultured in the 3-dimensional system. Here, we demonstrate modeling a 3-dimensional organ culture vascular system that recapitulates the in vivo physiological properties of resistance arteries. This platform holds on a substantial translational potential, not only for hypertension but also for other cardiovascular diseases where vascular-immune interfaces are established and relevant for onset and progression of the disease.