Loss of smooth muscle βENaC-mediated pressure-induced constriction promotes cerebrovascular inflammation and injury

INTRODUCTION: Pressure-induced constriction (PIC) is a key mechanism of cerebral blood flow autoregulation, where small arteries and arterioles constrict in response to elevations in intraluminal pressure. Loss of the PIC response in cerebral vascular disease has led to the hypothesis that the PIC response protects downstream microvessels from the damaging impact of exposure to systemic blood pressure. However, the lack of an animal model with a specific deficit in PIC responses without underlying vascular disease has limited direct evidence of the causative relationship between the PIC response and protection from vascular injury. Several lines of evidence from our laboratory have established the importance of the degenerin channel βENaC in the cerebral PIC responses. Thus, our laboratory developed a smooth muscle βENaC knockout mouse model to test the importance of PIC responsiveness in protection against vascular injury. MATERIALS AND METHODS: We examined vascular reactivity of middle cerebral artery segments to pressure, potassium chloride, and phenylephrine in male and female SMC-βENaC −/− and SMC-βENaC +/+ littermate control mice. Vascular injury was assessed by examining immune cell association with cerebral vessels, cytokine expression, and regional brain water content assessment. RESULTS: As expected, our findings showed that PIC, but not agonist-induced vasoconstriction, was abolished in cerebral vessels from SMC-βENaC −/− mice. Cerebral vessels from SMC-βENaC −/− mice showed elevated total CD45 + leukocytes, including monocyte–macrophages, neutrophils, and T and B lymphocytes, as well as elevated levels of certain chemokines and interleukins. Finally, SMC-βENaC −/− mice exhibited increased water content in the hippocampus. CONCLUSIONS: These findings provide evidence that the βENaC-mediated cerebral PIC response protects against cerebrovascular inflammation and injury.