GSE183588
A molecular complex of Cav1.2/CaMKK2/CaMK1a in caveolae is responsible for vascular remodeling through excitation-transcription coupling in vascular smooth muscle.
Elevation of intracellular Ca2+ ([Ca2+]i) activates Ca2+/calmodulin-dependent kinases (CaMK) and promotes gene transcription. This essential signaling pathway is referred to as excitation-transcription (E-T) coupling. Although vascular myocytes can exhibit E-T coupling, the molecular mechanisms and physiological/pathological roles are unknown. Multiscale analysis spanning from single molecules to whole organisms has revealed essential steps in mouse vascular smooth muscle E-T coupling: (1) Upon depolarizing stimulus Ca2+ influx through voltage-dependent Ca2+ channel Cav1.2 activates CaMKK2, which results in phosphorylation of CaMK1a and CREB in the nucleus. (2) Within caveolae the formation of molecular complex of Cav1.2/CaMKK2/CaMK1a is promoted in the vascular myocytes. (3) Ca2+ influx through Cav1.2 localized to caveolae  directly activates CaMKK2. (4) CaMK1a is phosphorylated by CaMKK2 at caveolae and translocated to the nucleus upon membrane depolarization. In addition, RNAseq analysis revealed that sustained depolarization of mesenteric artery preparation selectively induced genes related to chemotaxis, leukocyte adhesion and inflammation, and these changes were reversed by inhibitors of Cav1.2, CaMKK2 and CaMK or disruption of caveolae. In the context of pathophysiology, when mesenteric artery was loaded by high pressure in vivo, we noted CREB phosphorylation in myocytes, macrophage accumulation at adventitia, and increased thickness and cross-sectional area of tunica media. These changes were reduced in caveolin1-KO mice or in mice treated with a CaMKK2 inhibitor STO609. In summary, E-T coupling depend on Cav1.2/CaMKK2/CaMK1a localized to caveolae, and this molecular complex converts [Ca2+]i changes to gene transcription, leading to macrophage accumulation and media remodeling for adaptation to increased circumferential stretch. Overall design: Mesenteric artery mRNA profiles of 10 weeks old wild type (WT) mice