Microphysiological uremia model reveals biophysical potentiators of vascular dysfunction

Abstract

Cardiovascular disease is a leading cause of mortality in individuals with chronic kidney disease. Hypertension, common among patients with chronic kidney disease, is a major contributor to both kidney damage and the heightened cardiovascular risk in these patients. Advanced chronic kidney disease is associated with elevated levels of circulating uremic toxins, particularly indoxyl sulfate and p-cresyl sulfate, and are known to exacerbate cardiovascular risk by promoting inflammatory processes, including monocyte adhesion, rolling, and extravasation. However, despite the established link between chronic kidney disease and cardiovascular disease, the specific role of uremic toxins in monocyte-endothelial interactions in hypertensive settings remains largely underexplored. In this study, we developed a 3D microfluidic model to examine the effects of indoxyl sulfate on monocyte adhesion and extravasation across engineered microvessels embedded in collagen hydrogels with different densities under controlled luminal pressure. We found that elevated pressure alone significantly enhanced monocyte adhesion and extravasation, regardless of matrix density, and that the uremic environment further increased these effects. Additionally, denser hydrogels primed THP-1 monocyte cells toward a pro-inflammatory like phenotype with reduced phagocytic capacity, while softer hydrogels induced an anti-inflammatory like phenotype with enhanced phagocytosis. However, exposure to the uremic environment diminished phagocytosis and shifted cells toward a pro-inflammatory like state, irrespective of matrix density. The presented approach has the potential to experimentally dissect multiple factors that contribute to elevated cardiovascular risks in chronic kidney disease patients and improve the understanding of mechanisms involved in monocyte dynamics in chronic kidney disease- related cardiovascular disease.