Abstract
BACKGROUND: Vascular restenosis, a common complication following vascular reconstruction, results in stenosis or blockage that impairs vascular remodeling. This process is driven by the activation of vascular stem cells. Growing evidence suggests that intermediate conductance calcium-activated potassium (IK(Ca)) channels play a crucial role in regulating the function of these cells. This study aims to explore how IK(Ca) channels influence Sca-1(+) (stem cell antigen-1 positive) stem cells in the context of vascular anastomotic restenosis. METHODS: To investigate the role and mechanism of the IK(Ca) channel in Sca-1(+) cell activation and its involvement in vascular anastomosis restenosis, we assessed the impact of IK(Ca) channel deficiency on the vascular restenosis-promoting ability of Sca-1(+) cells using a mouse femoral artery anastomosis model. Mechanistic insights were gained through patch-clamp electrophysiology, intracellular Ca(2+) measurement, and molecular biology techniques. RESULTS: Genetic deletion of IK(Ca) channels in IK(Ca)(-/-) mice led to reduced neointimal formation and decreased proliferation of Sca-1(+) cells at the anastomotic site. In vitro studies confirmed the presence of functional IK(Ca) channels in Sca-1(+) cells and demonstrated that IK(Ca) and TRPC1 (transient receptor potential canonical 1) channels cooperate in regulating membrane potential and intracellular Ca(2+) levels. Furthermore, our findings suggest that IK(Ca) channel-mediated modulation of ERK (extracellular signal-regulated kinase) and p38 phosphorylation underpins a key signaling mechanism in this process. CONCLUSIONS: This study clarifies the role of the IK(Ca)-TRPC1-Ca(2+) pathway in activating vascular Sca-1(+) cells and establishes the contribution of the IK(Ca) channel to vascular restenosis development. Understanding how IK(Ca) channels affect the function of vascular Sca-1(+) cells provides valuable insights into the complex mechanisms of vascular remodeling during vascular stenosis.