Journal
PLOS ONE
Volume 8, Issue 8, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0071550
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Funding
- American Heart Association [0930086N]
- National Institutes of Health (NIH) [RO1 HL 108932]
- Department of Veterans Affairs
- Department of Veterans Affairs, Office of Research and Development, Biomedical Laboratory Research and Development [1BX000163-01]
- NIH [RO1 HL 079031, R01 HL 070250, RO1 AA 019568]
- NIH
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL096652, T32HL007121, R01HL070250, R01HL079031, R01HL108932] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007337] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [R01AA019568] Funding Source: NIH RePORTER
- Veterans Affairs [I01BX000163] Funding Source: NIH RePORTER
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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.
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