No abstract

Elastin insufficiency leads to the cardiovascular hallmarks of the contiguous gene deletion disorder, Williams-Beuren syndrome, including hypertension and vascular stiffness. Previous studies showed that Williams-Beuren syndrome deletions that extended to include the NCF1 gene were associated with lower blood pressure and reduced vascular stiffness. NCF1 encodes for p47phox, the regulatory component of the NOX1 NADPH oxidase complex, that generates reactive oxygen species in the vascular wall. Dihydroethidium and 8-hydroxyguanosine staining of mouse aortas confirmed that Eln heterozygotes (Eln+/-) had greater reactive oxygen species (ROS) levels than wild types (Eln+/+), a finding that was negated in vessels cultured without hemodynamic stressors. To analyze the Nox effect on elastin insufficiency, we utilized both genetic and chemical manipulations. Both Ncf1 haploinsufficiency (Ncf1+/-) and Nox1 insufficiency (Nox1-/y) decreased oxidative stress and systolic blood pressure in Eln+/- without modifying vascular structure. Chronic treatment with apocynin, a p47phox inhibitor, lowered systolic blood pressure in Eln+/-, but had no impact on Eln+/+ controls. In vivo dosing with phenylephrine produced an augmented blood pressure response in Eln+/- relative to Eln+/+, and genetic modifications or drug-based interventions that lower Nox1 expression reduce the hypercontractile response to phenylephrine in Eln+/- mice to Eln+/+ levels. These results indicate that the mechanical and structural differences caused by elastin insufficiency leading to oscillatory flow can perpetuate oxidative stress conditions which are linked to hypertension, and that by lowering the Nox1-mediated capacity for vascular ROS production, blood pressure differences can be normalized.

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 risk of Alzheimer's disease. However, it is unknown whether 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 vasoconstrictor 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 whether 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 wild‐type (Eln+/+) mice. Here, we used this model to examine the relationship between large elastic artery stiffness and resistance artery vasoconstrictor responses. In middle cerebral arteries (MCAs), vasoconstriction in response 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, Eln+/− and Eln+/+ mice did not differ in the response to Ang II. In addition, the vasoconstrictor responses to noradrenaline, endothelin‐1 and potassium chloride were not different between Eln+/− and Eln+/+ mice for either MCAs or gastrocnemius feed arteries. The MCA AT1R gene expression did not differ between groups, whereas Ang II type 2 receptor gene expression was ∼50% lower in MCAs from Eln+/− versus Eln+/+ mice (P = 0.01). In conclusion, greater large elastic artery stiffness is associated with an exacerbated vasoconstriction response to Ang II in cerebral arteries, but is not associated with the responses to other vasoconstrictors in either cerebral or skeletal muscle feed arteries.