Reconstitution of Autophagy Ameliorates Endothelium-Dependent Relaxation, Vascular Smooth Muscle Calcium Sensitization, & Arterial Stiffening in Spontaneously Hypertensive Rats

Insufficient autophagy has been proposed as a mechanism of cellular aging, as this leads to the accumulation of dysfunctional macromolecules and organelles. Premature vascular aging occurs in hypertension. In fact, many factors that contribute to the deterioration of vascular function as we age are accelerated in clinical and experimental hypertension. Previously, we have reported decreased autophagic activity in arteries from spontaneously hypertensive rats (SHR); however, the effects of restoring autophagic activity on blood pressure and vascular function are currently unknown. We hypothesized that reconstitution of arterial autophagy in SHR would decrease blood pressure and improve endothelium-dependent relaxation. We treated 13-18 week old Wistar and SHR with autophagy activator trehalose (2% in drinking water) for 28 days. Blood pressure was measured by telemetry and vascular function was performed on isolated mesenteric resistance arteries using wire and pressure myographs. Treatment with trehalose had no effect on mean arterial pressure in SHR (p>0.05). Trehalose treatment in SHR improved the relaxation to acetylcholine (ACh) [%Relaxation (ACh 1 μM), vehicle: 59.6±8.4 vs. trehalose: 82.4±4.2; p<0.05], and this was not different from arteries incubated with cyclooxygenase inhibitor indomethacin and reactive oxygen species scavenger tempol [%Relaxation (ACh 1 μM), trehalose: 82.4±4.2 vs. vehicle+indomethacin: 92.7±3.9 and vehicle+tempol: 89.3±5.4; both p>0.05]. Trehalose treatment in SHR also prevented the relaxation to Rho kinase inhibition [%Relaxation (Y-27632 0.3 μM), vehicle: 30.4±4.3 vs. trehalose: 8.4±3.5; p<0.05]. Finally, trehalose treatment in SHR decreased arterial stiffness as indicated by the slope of the stress-strain curve [β (stress-strain), vehicle: 8.3±0.6 vs. trehalose: 5.5±0.2; p<0.05]. Overall these data indicate that reconstitution of arterial autophagy in SHR improves endothelial and vascular smooth muscle function, which could synergize to prevent arterial stiffening. As a result, restoration of arterial autophagic activity could be a novel therapeutic for premature vascular aging in hypertension, a recently adopted clinical guideline for cardiovascular disease prevention.