The Multifunctional Ca2+/Calmodulin-Dependent Kinase II delta (CaMKII delta ) Regulates Arteriogenesis in a Mouse Model of Flow-Mediated Remodeling. e71550

• Published in: PloS one 2013-08, Vol.8 (8)
• Main Authors: Scott, Jason A, Klutho, Paula J, Accaoui, Ramzi El, Nguyen, Emily, Venema, Ashlee N, Xie, Litao, Jiang, Shuxia, Dibbern, Megan, Scroggins, Sabrina, Prasad, Anand M
• Format: Article
• Language: English
• Subjects: Allografts
• ISSN: 1932-6203
• DOI: 10.1371/journal.pone.0071550

Objective Sustained 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 Results Ligation 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 CaMKII delta (CaMKII delta -/-) 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 CaMKII delta -/- mice. MMP9 mainly colocalized with adventitial macrophages. In contrast, we did not observe an effect of CaMKII delta deficiency on other proposed mediators of arteriogenesis such as expression of adhesion molecules or smooth muscle proliferation. Transplantation of WT bone marrow into CaMKII delta -/- mice normalized flow-mediated remodeling. Conclusion CaMKII delta 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.