Rathod Mitesh, Stack Ryan N, Kubik Sarah E, Huang Stephanie A, Whitworth Chloe P, Aw Wen Y, Doherty Elizabeth L, Meehan Sara M, Roy-Chaudhury Prabir, Polacheck William J
Lampe Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, 10010 Mary Ellen Jones Building, 116 Manning Drive, Chapel Hill, NC, 27514, USA.
Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill School of Medicine, 130 Mason Farm Road, Chapel Hill, NC, 27599, USA.
Adv Sci (Weinh). 2025 Sep;12(33):e17091. doi: 10.1002/advs.202417091. Epub 2025 Jun 20.
Cardiovascular disease is a leading cause of mortality in individuals with chronic kidney disease (CKD), with hypertension being a major contributor to both kidney damage and increased cardiovascular risk. Despite the established link between CKD and cardiovascular disease, the role of uremic toxins in monocyte-endothelial interactions under hypertensive conditions remains underexplored. Here, a 3D microfluidic model is developed to examine the effects of indoxyl sulfate on monocyte adhesion and extravasation across engineered microvessels embedded in hydrogels with different densities under controlled luminal pressure. Elevated pressure alone in absence of indoxyl sulfate significantly enhanced monocyte adhesion and extravasation, regardless of matrix density, while matrix density regulated adhesion and transmigration in the uremic environment. ICAM-1 is identified as a key driver of THP-1 monocyte adhesion to the endothelium. Additionally, denser hydrogels primed monocytes toward a pro-inflammatory phenotype with reduced phagocytic capacity, while softer hydrogels induced an anti-inflammatory-like phenotype with enhanced phagocytosis. However, the uremic environment reduced phagocytosis and shifted cells toward a pro-inflammatory-like state, irrespective of matrix density. This approach has the potential to dissect multiple factors that contribute to elevated cardiovascular risks in CKD patients and improve the understanding of mechanisms involved in monocyte dynamics in CKD-related cardiovascular disease.
心血管疾病是慢性肾脏病（CKD）患者死亡的主要原因，高血压是导致肾脏损害和心血管风险增加的主要因素。尽管CKD与心血管疾病之间的联系已得到证实，但尿毒症毒素在高血压条件下单核细胞与内皮细胞相互作用中的作用仍未得到充分研究。在此，开发了一种三维微流控模型，以研究硫酸吲哚酚对在受控管腔内压力下嵌入不同密度水凝胶中的工程化微血管上单核细胞黏附和渗出的影响。在不存在硫酸吲哚酚的情况下，仅压力升高就显著增强了单核细胞的黏附和渗出，而与基质密度无关，而基质密度在尿毒症环境中调节黏附和迁移。ICAM-1被确定为THP-1单核细胞黏附于内皮的关键驱动因素。此外，密度较高的水凝胶使单核细胞向促炎表型转变，吞噬能力降低，而较软的水凝胶诱导出具有增强吞噬作用的抗炎样表型。然而，尿毒症环境降低了吞噬作用，并使细胞向促炎样状态转变，而与基质密度无关。这种方法有可能剖析导致CKD患者心血管风险升高的多种因素，并增进对CKD相关心血管疾病中单核细胞动态变化所涉及机制的理解。
