Minoxidil improves vascular compliance, restores cerebral blood flow and alters extracellular matrix gene expression in a model of chronic vascular stiffness

Increased vascular stiffness correlates with higher risk of cardiovascular complications in aging adults. Elastin insufficiency, as observed in patients with Williams-Beuren syndrome or with familial supravalvular aortic stenosis, also increases vascular stiffness and leads to arterial narrowing. We used Eln+/- mice to test the hypothesis that pathologically increased vascular stiffness with concomitant arterial narrowing leads to decreased blood flow to end organs such as the brain. We also hypothesized that drugs which remodel arteries and increase lumen diameter would improve flow. To test these hypotheses, we compared carotid blood flow using ultrasound and cerebral blood flow using MRI-based arterial spin labeling in WT and Eln+/- mice. We then studied how minoxidil, a KATP channel opener and vasodilator, affects vessel mechanics, blood flow and gene expression. Both carotid and cerebral blood flows were lower in Eln+/- than in WT mice. Treatment of Eln+/- mice with minoxidil lowered blood pressure and reduced functional arterial stiffness to WT levels. Minoxidil also improved arterial diameter and restored carotid and cerebral blood flows in Eln+/- mice. Beneficial effects persisted for weeks after drug removal. RNA-Seq analysis revealed differential expression of 127 extracellular matrix-related genes among the treatment groups. These results indicate that elastin insufficiency impairs end organ perfusion, which may contribute to increased cardiovascular risk. Minoxidil, despite lowering blood pressure, improves end organ perfusion. Changes in matrix gene expression and persistence of treatment effects after drug withdrawal suggest arterial remodeling. Such remodeling may benefit patients with genetic or age-dependent elastin insufficiency