Matrix metalloproteinase 2 and 9 dysfunction underlie vascular stiffness in circadian clock mutant mice.
OBJECTIVE
To determine if elasticity in blood vessels is compromised in circadian clock-mutant mice (Bmal1-knockout [KO] and Per-triple KO) and if matrix metalloproteinases (MMPs) might confer these changes in compliance.


RESULTS
High-resolution ultrasonography in vivo revealed impaired remodeling and increased pulse-wave velocity in the arteries of Bmal1-KO and Per-triple KO mice. In addition, compliance of remodeled arteries and naïve pressurized arterioles ex vivo from Bmal1-KO and Per-triple KO mice was reduced, consistent with stiffening of the vascular bed. The observed vascular stiffness was coincident with dysregulation of MMP-2 and MMP-9 in Bmal1-KO mice. Furthermore, inhibition of MMPs improved indexes of pathological remodeling in wild-type mice, but the effect was abolished in Bmal1-KO mice.


CONCLUSIONS
Circadian clock dysfunction contributes to hardening of arteries, which may involve impaired control of the extracellular matrix composition.
Anea
Ciprian B
CB
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA, USA.
Ali
M Irfan
MI
Osmond
Jessica M
JM
Sullivan
Jennifer C
JC
Stepp
David W
DW
Merloiu
Ana M
AM
Rudic
R Daniel
RD
D056930:ARNTL Transcription Factors / Q000172:deficiency / Q000235:genetics; D000818:Animals; D001794:Blood Pressure; D002339:Carotid Arteries / Q000000981:diagnostic imaging / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D002340:Carotid Artery Diseases / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D002478:Cells, Cultured; D057906:Circadian Clocks / Q000235:genetics*; D004548:Elasticity; D042783:Endothelial Cells / Q000201:enzymology; D005109:Extracellular Matrix / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D032389:Myocytes, Smooth Muscle / Q000201:enzymology; D056950:Period Circadian Proteins / Q000172:deficiency / Q000235:genetics; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D013997:Time Factors; D018617:Ultrasonography, Doppler, Pulsed
D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse; D061965:Matrix Metalloproteinase Inhibitors; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; C512645:Per3 protein, mouse; D056950:Period Circadian Proteins; D011480:Protease Inhibitors; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse