Small artery mechanics in hyperhomocysteinemic mice: effects of angiotensin II.
OBJECTIVE
Elevated plasma homocysteine has been associated with cardiovascular disease, although a causal relationship is unclear. The purpose of this study was to evaluate whether mild hyperhomocysteinemia (H-Hcy) may increase vascular stiffness of small arteries.


METHODS
Wild-type (+/+) and heterozygous (+/-) methylenetetrahydrofolate reductase (Mthfr) knockout mice, a new model of mild H-Hcy, were treated with vehicle or angiotensin (Ang) II infusion (400 ng/kg per min s.c.). Second-order mesenteric arteries were studied on pressurized myograph. They were exposed to intraluminal pressures ranging from 3 to 140 mmHg. Media thickness and lumen diameter were measured at each pressure level to determine wall mechanical properties. Collagen type I/III and elastin deposition in the vascular wall were evaluated by confocal immunofluorescence microscopy.


RESULTS
Media-to-lumen ratio was similar in Mthfr and Mthfr mice, and significantly increased by Ang II. The stress-strain relationship was shifted to the left in small mesenteric arteries from Mthfr compared to Mthfr mice, indicating that mild H-Hcy is associated with stiffer vessels. Ang II treatment in Mthfr mice enhanced the leftward shift in the stress-strain relationship and significantly increased the elastic modulus, suggesting the presence of stiffer wall components in small arteries in these animals. Increased collagen type I/III accumulation and decreased elastin content in the media of mesenteric arteries was noted in Mthfr compared to Mthfr mice. Ang II infusion augmented vascular collagen deposition in both groups, more substantially in Mthfr mice.


CONCLUSIONS
Mild hyperhomocysteinemia is associated with stiffer small arteries with increased collagen deposition in the media. These changes are accentuated by Ang II-induced blood pressure elevation.
Neves
Mario F
MF
Canadian Institutes of Health Research, Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, 110 Pine Avenue West, Montreal, Quebec, Canada H2W 1R7.
Endemann
Dierk
D
Amiri
Farhad
F
Virdis
Agostino
A
Pu
Qian
Q
Rozen
Rima
R
Schiffrin
Ernesto L
EL
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism; D005260:Female; D006710:Homocysteine / Q000097:blood; D020138:Hyperhomocysteinemia / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D014662:Vasoconstrictor Agents; D006710:Homocysteine; D000804:Angiotensin II; D003094:Collagen; D004549:Elastin; D042965:Methylenetetrahydrofolate Reductase (NADPH2)