Myogenic Activation and Endothelial Function in Cerebral Arteries with Metabolic Disease: Is Myogenic Tone Protective for the Endothelium?

Abstract

While it has been well established that the development of metabolic disease, including hypertension, impaired glycemic control, etc. can be associated with increased myogenic activation of cerebral resistance arteries and arterioles, the impact of this shift in pressure‐induced responses on integrated vascular function remains elusive. Using male obese Zucker rats (OZR) at 17–18 weeks of age, we determined that changes to myogenic activation of ex vivo pressurized middle cerebral arteries (MCA) was best predicted by the severity of elevation in mean arterial pressure and allowed for stratification into three groups (mild, moderate, high degrees of elevation in the slope of myogenic activation vs. intravascular pressure). While dilator responses to endothelium‐dependent stimuli (e.g., acetylcholine) were attenuated in all MCA of OZR, the severity of the attenuation was correlated with the degree of increase in myogenic activation from normal for that vessel. Treatment of the vessels with the anti‐oxidant TEMPOL significantly improved vascular responses to acetylcholine in the mild and moderate myogenic activation groups of MCA from OZR, but had minimal impact on high myogenic response groups. In contrast, treatment of vessels with the mechanosensitive cation channel inhibitor gadolinium chloride to reduce myogenic activation in OZR MCA to levels comparable to that of control LZR had minimal impact on endothelial function in MCA from the mild and moderate groups, but significantly improved endothelium‐dependent responses in MCA from the high group. Combined treatment of OZR MCA with both gadolinium chloride and TEMPOL resulted in endothelium‐dependent responses being very comparable across groups. Assays for vascular nitric oxide and PGI2 bioavailability provided correlative evidence that endothelial function, while still impaired in OZR in general, may be better maintained in vessels from animals with a higher myogenic activation than would have otherwise been predicted. Calculations suggest that the increased myogenic activation in the “high” group may serve to reduce wall tension in response to the elevated arterial pressure and that this may contribute to a mechanism that partially protects endothelial function. Support or Funding Information CIHR #389769; NSERC RGPIN‐2017‐04536 and RGPIN‐2018‐05450