Cerebral and skeletal muscle feed artery vasoconstrictor responses in a mouse model with greater large elastic artery stiffness.

NEW FINDINGS: What is the central question of this study? Greater large artery stiffness is associated with dysfunctional resistance artery vasodilatory responses, impaired memory and greater Alzheimer's disease risk. However, it is unknown if stiffer large arteries affect cerebral and skeletal muscle feed artery responses to vasoconstrictors. What is the main finding and its importance? In a mouse model with greater large artery stiffness (Eln+/- ), we find an exacerbated vasoconstriction response to angiotensin II in cerebral arteries, but not skeletal muscle feed arteries, thus implicating altered cerebral artery angiotensin II responsiveness in the poor brain outcomes associated with greater large artery stiffness.

ABSTRACT: Greater stiffness of the large elastic arteries is associated with end-organ damage and dysfunction. At the same time, resistance artery vasoconstrictor responsiveness influences vascular tone and organ blood flow. However, it is unknown if large elastic artery stiffness modulates the responsiveness to vasoconstrictors in resistance arteries of the cerebral or skeletal muscle circulations. We previously described the elastin haploinsufficient (Eln+/- ) mouse as a model with greater aortic stiffness, but with similar cerebral and skeletal muscle feed artery stiffness to wildtype (Eln+/+ ) mice. Here, we utilized this model to examine the relation between large elastic artery stiffness and resistance artery vasoconstrictor responses. In middle cerebral arteries (MCAs), vasoconstriction to angiotensin II (Ang II) was ∼40% greater in Eln+/- compared with Eln+/+ mice (p = 0.02), and this group difference was ameliorated by losartan, indicating a role for Ang II type 1 receptors (AT1Rs). In gastrocnemius feed arteries (GFAs), Eln+/- and Eln+/+ mice did not differ in the response to Ang II. In addition, the vasoconstrictor responses to norepinephrine, endothelin-1, and potassium chloride were not different between Eln+/- and Eln+/+ mice for either MCAs or GFAs. MCA AT1R gene expression did not differ between groups, while Ang II type 2 receptor gene expression was ∼50% lower in MCAs from Eln+/- vs. Eln+/+ (p = 0.01). In conclusion, greater large elastic artery stiffness is associated with an exacerbated vasoconstriction response to Ang II in cerebral arteries, but not associated with the responses to other vasoconstrictors in cerebral or skeletal muscle feed arteries. This article is protected by copyright. All rights reserved.