The Multifunctional Ca2+/Calmodulin-Dependent Kinase IIδ (CaMKIIδ) Regulates Arteriogenesis in a Mouse Model of Flow-Mediated Remodeling

Abstract

ObjectiveSustained hemodynamic stress mediated by high blood flow promotes arteriogenesis, the outward remodeling of existing arteries. Here, we examined whether Ca2+/calmodulin-dependent kinase II (CaMKII) regulates arteriogenesis.Methods and ResultsLigation of the left common carotid led to an increase in vessel diameter and perimeter of internal and external elastic lamina in the contralateral, right common carotid. Deletion of CaMKIIδ (CaMKIIδ−/−) abolished this outward remodeling. Carotid ligation increased CaMKII expression and was associated with oxidative activation of CaMKII in the adventitia and endothelium. Remodeling was abrogated in a knock-in model in which oxidative activation of CaMKII is abolished. Early after ligation, matrix metalloproteinase 9 (MMP9) was robustly expressed in the adventitia of right carotid arteries of WT but not CaMKIIδ−/− mice. MMP9 mainly colocalized with adventitial macrophages. In contrast, we did not observe an effect of CaMKIIδ deficiency on other proposed mediators of arteriogenesis such as expression of adhesion molecules or smooth muscle proliferation. Transplantation of WT bone marrow into CaMKIIδ−/− mice normalized flow-mediated remodeling.ConclusionCaMKIIδ is activated by oxidation under high blood flow conditions and is required for flow-mediated remodeling through a mechanism that includes increased MMP9 expression in bone marrow-derived cells invading the arterial wall.

Repetitive Transient Ischemia-Induced Cardiac Angiogenesis is Mediated by Camkii Activation

“…CaMKII is a known pro-arrhythmic molecule and a key mediator of heart failure [20,21]. CaMKII also participated in artery remodeling through vascular smooth muscle cells [22]. In the present study, we have revealed an important role of CaMKII activation in the ischemiainduced coronary angiogenesis.…”

Role of CaMKII in Ang-II-dependent small artery remodeling

“…Moreover, VSMC undergo profound changes in protein expression profiles, including CaMKII isoforms, when isolated from the vascular wall and grown in culture [48]. In this study, Ang-II infusion led to relatively minor changes in CaMKII isoform expression compared to other disease models or as seen after cell isolation [19, 20, 48]. Emerging data that CaMKII isoforms have divergent [21], if not opposing functions imply that CaMKII signaling is cell- and context-specific.…”

“…In previous studies, CaMKII phosphorylation enhanced DNA binding of SRF in skeletal muscle [15], whereas the related calcium/calmodulin-dependent kinase IV repressed SRF activity in cardiac myocytes [44]. Alternatively, CaMKII inhibition may exert its actions through regulation of mRNA stability [20, 45]. Of note, we previously reported that CaMKII inhibition in the aortic wall in vivo promotes the expression of mRNA’s related to contractile muscle fiber [23].…”

CAMKIIγ suppresses an efferocytosis pathway in macrophages and promotes atherosclerotic plaque necrosis

“…If the resolution process is improved in M-CaMKII-KO lesions, as we predict, this might explain the improvement in protective fibrous cap formation (45). However, it is also possible that M-CaMKII-KO directly inhibits expression or activity of matrix metalloproteinases (see Figure 2E) (46,47), which have been implicated in advanced plaque progression (48,49). Another possible link between inflammation resolution and the findings reported herein is that efferocytosis in general, and MerTK signaling in parNo significant change in Nr1h2 (LXR) was observed.…”