血管平滑筋細胞の興奮-転写連関を介した血管リモデリング形成機構の解明

抄録

Various stresses loaded on the arteries induce vascular remodeling. Macrophages accumulated in the vascular wall promote dedifferentiation and proliferation of smooth muscle cells (SMC) and induce vascular remodeling. However, it remains unclear how arteries sense various stresses and accumulate macrophages. We found that Ca²⁺ signals in SMCs are converted into gene transcription via excitation-transcription (E-T) coupling, which recruits macrophages to the vascular wall. Imaging analyses revealed that the activation of a complex consisting of voltage-dependent Ca²⁺ channel (Cav1.2), Ca²⁺/CaM dependent kinase kinase (CaMKK)-2, and CaMK1α formed in caveolae induces transcription of genes, such as chemokines, cytokines, and leukocyte adhesion molecules. When pressure overload was applied to mouse mesenteric arteries in vivo, migration of macrophages to the vascular adventitia and medial hypertrophy were detected. These changes were attenuated in deletion of caveolin-1 or CaMKK2 genes as well as the administration of a CaMKK2 inhibitor. These data suggest that the sustained increase in intracellular Ca²⁺ level due to mechanical stress is converted into the transcription of proinflammatory genes through E-T coupling, which results in the accumulation of macrophages and subsequent inflammation causes vascular remodeling.