The purpose of this grant is to investigate the role of Acid Sensing Ion Channels (ASIC) in myogenic constriction of mouse cerebral arteries. Pressure-induced constriction is an inherent response present in certain vessels, including cerebral blood vessels. This property of cerebral blood vessels is a critical homeostatic regulator of changes in mean arterial pressure occurring during normal activities as well as in pathologic states involving hypertension or hypotension. Many studies have evaluated cerebral blood flow showing preserved autoregulation and protection of the brain from increased pressure, while other studies have shown impairment of autoregulation resulting in injury. As more is learned about pathologic conditions affecting the brain, it is important to study the impact of cerebral blood flow and autoregulation so that we may better understand and protect the brain from increases in pressure. While pressure-induced constriction (myogenic constriction) has been well documented, the mechanisms by which vascular smooth muscle cells (VSMC) sense mechanical stretch, the first step leading to mechanically-gated increases in Na+ / Ca+ influx, is unknown. Recent evidence has shown that Degenerin/Epithelial Sodium Channels (DEG/ENaC) form mechanosensative channels in smooth muscle and neurons. The ASIC proteins, a group of H+-gated cation channels, are a subgroup of the DEG/ENaC family. Although genetic evidence suggests ASIC2 acts as a mechanosensor in sensory neurons, it is unknown if ASIC2 can act as a mechanosensor and mediate myogenic constriction in cerebral arteries. To study the role of ASIC2 in myogenic constriction in cerebral arteries of mice, the presence of the proteins will be determined using RT-PCR and quantitative immunolabeling. The ASIC2 null mouse model will be used to study the vascular response to changes in pressure as well as measure the regulation of ion transients in isolated middle cerebral and basilar arteries.
|Gannon, Kimberly P; McKey, Susan E; Stec, David E et al. (2015) Altered myogenic vasoconstriction and regulation of whole kidney blood flow in the ASIC2 knockout mouse. Am J Physiol Renal Physiol 308:F339-48|
|Gannon, Kimberly P; Vanlandingham, Lauren G; Jernigan, Nikki L et al. (2008) Impaired pressure-induced constriction in mouse middle cerebral arteries of ASIC2 knockout mice. Am J Physiol Heart Circ Physiol 294:H1793-803|