Abstract 20330: Cerebral Artery Dysfunction in a Mouse Model of Greater Large Artery Stiffness
Advancing age, as well as diseases such as diabetes, are characterized by increased large artery stiffness and increased cerebrovascular disease risk. It has been hypothesized that cerebral artery dysfunction connects these events; however a cause-and-effect relation between large artery stiffening and altered cerebral artery dilation and constriction has not been established. We studied elastin heterozygous mice (Eln+/-) as a model of increased large artery stiffness without co-morbidity. Eln+/- mice had ~35% greater aortic stiffness (pulse wave velocity) compared with Eln+/+ (p=0.04), but stiffness of the middle cerebral artery (MCA, ex vivo passive response) was similar between groups (p>0.05). MCA endothelium-dependent dilation (EDD), assessed by the maximal dilation to acetylcholine, was ~40% lower in Eln+/- compared with Eln+/+ (p<0.001). After incubation with nitric oxide (NO) synthase inhibitor L-NAME, EDD did not differ between groups (p>0.05), indicating that reduced NO bioavailability mediated the impaired EDD in Eln+/-. Nitrotyrosine content, a marker of oxidative stress, was ~40% higher in MCAs from Eln+/- compared with Eln+/+ (p=0.04). After incubation with superoxide scavenger TEMPOL, EDD improved by ~65% in Eln+/- (p=0.002), but was unchanged in Eln+/+ (p>0.05). In MCAs, the response to angiotensin II (AngII) was biphasic, with constriction at lower doses and dilation at higher doses. Eln+/- MCAs had ~40% greater constriction (p=0.03) and ~20% lower dilation (p=0.03) to AngII compared to Eln+/+. After incubation with L-NAME, the dilatory response to AngII did not differ between groups (p>0.05), indicating that reduced NO bioavailability mediated the impaired dilatory response to AngII in Eln+/-. The maximal constriction to norepinephrine, endothelin-1, and potassium chloride did not differ between groups (P>0.05). These results indicate that greater large artery stiffness induces cerebral artery dysfunction; specifically, impaired MCA dilation to AngII and endothelium-dependent stimuli as a result of reduced NO bioavailability and increased oxidative stress. Thus, interventions that target the mechanisms and/or consequences of large artery stiffness may be important for reducing cerebrovascular disease risk.
Author Disclosures: A.E. Walker: None. G.D. Henson: None. K.D. Reihl: None. P.S. Dobson: None. E.I. Nielson: None. J. Ling: None. D.Y. Li: None. L.A. Lesniewski: None. A.J. Donato: None.
- © 2014 by American Heart Association, Inc.