The multifunctional Ca²⁺/calmodulin-dependent kinase IIδ (CaMKIIδ) regulates arteriogenesis in a mouse model of flow-mediated remodeling.
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.


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 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.


CONCLUSIONS
CaMKIIδ 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.
Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
Jason A
JA
Scott
Paula J
PJ
Klutho
Ramzi
R
El Accaoui
Emily
E
Nguyen
Ashlee N
AN
Venema
Litao
L
Xie
Shuxia
S
Jiang
Megan
M
Dibbern
Sabrina
S
Scroggins
Anand M
AM
Prasad
Elisabeth D
ED
Luczak
Melissa K
MK
Davis
Weiwei
W
Li
Xiaoqun
X
Guan
Johannes
J
Backs
Annette J
AJ
Schlueter
Robert M
RM
Weiss
Francis J
FJ
Miller
Mark E
ME
Anderson
Isabella M
IM
Grumbach
D000818:Animals; D016026:Bone Marrow Transplantation; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism*; D020212:Carotid Artery Injuries / Q000000981:diagnostic imaging / Q000201:enzymology; D017536:Carotid Artery, Common / Q000000981:diagnostic imaging / Q000502:physiology* / Q000648:ultrastructure; D002478:Cells, Cultured; D004789:Enzyme Activation; D017353:Gene Deletion; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D010084:Oxidation-Reduction; D014463:Ultrasonography; D015854:Up-Regulation
D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D020780:Matrix Metalloproteinase 9