Impact of IK Ca Channel on CD34 + Cells in Angiotensin II-Induced Arteriole Remodeling of Hypertensive Mice

BACKGROUND: Mechanisms of endothelial repair in hypertension remain unclear. CD34 + cells are reported to contribute to vascular regeneration; however, their origin and regulation in hypertension are poorly understood. We investigated the role of IK Ca channels in CD34 + cell-mediated endothelial repair during Ang II (angiotensin II)-induced arteriole remodeling. METHODS: Using inducible lineage tracing (Cd34-CreERT2; R26-tdTomato), we tracked nonbone marrow-derived CD34 + cells in hypertensive mice. Single-cell RNA sequencing, immunofluorescence, transwell migration assays, and patch-clamp techniques were used to analyze phenotypic transitions, ion channel activity, and signaling pathways. Bone marrow transplantation, the IK Ca channel inhibitor TRAM-34, and the ERK (extracellular signal-regulated kinase) inhibitor PD98059 were used to validate functional mechanisms. RESULTS: Lineage tracing revealed that nonbone marrow-derived CD34 + cells contributed to endothelial repair under hypertensive conditions. Immunofluorescence analysis showed an increase in CD31 + -tdTomato + cells in the arterioles of Ang II-treated mice after 6 weeks, indicating improved endothelial integrity. Single-cell RNA sequencing revealed 2 subgroups of endothelial cells, one of which expressed stem cell markers such as CD34 (cluster of differentiation 34), Flk-1 (fetal liver kinase 1), and Sca-1 (stem cell antigen-1). Gene expression analysis showed that CD34 + cells are involved in endothelial repair through the regulation of cell migration. Importantly, IK Ca channel activation facilitated CD34 + cell migration, and TRAM-34-based inhibition of IK Ca channels reduced migration. Mechanistic studies revealed that Ang II enhanced CD34 + cell migration via IK Ca -mediated activation of the ERK/P38 signaling pathway, promoting cytoskeletal reorganization and increased intracellular calcium levels. CONCLUSIONS: Arteriole-resident CD34 + cells contribute to endothelial repair in Ang II-induced hypertension. Moreover, IK Ca channel upregulation facilitates CD34 + cell migration via ERK/P38 signaling, suggesting potential therapeutic targets for hypertension.