Impaired intracellular Ca2+signaling contributes to age-related cerebral small vessel disease inCol4a1mutant mice

Abstract

AbstractHumans and mice with mutations inCOL4A1andCOL4A2manifest hallmarks of cerebral small vessel disease (cSVD), but the pathogenic mechanisms are largely unknown. Mice with a missense mutation inCol4a1at amino acid 1344 (Col4a1+/G1344D) exhibited age-dependent intracerebral hemorrhage (ICH) and brain lesions. Here we report that this pathology was associated with the loss of myogenic vasoconstriction, an intrinsic vascular response essential for the autoregulation of cerebral blood flow. Electrophysiological analyses showed that the loss of myogenic constriction resulted from blunted pressure-induced smooth muscle cell (SMC) membrane depolarization. Further, we found that dysregulation of membrane potential was associated with impaired Ca2+-dependent activation of large-conductance Ca2+-activated K+(BK) and transient receptor potential melastatin 4 (TRPM4) cation channels linked to disruptions in sarcoplasmic reticulum (SR) Ca2+signaling. TreatingCol4a1+/G1344Dmice with 4-phenylbutyrate, a compound that promotes the trafficking of misfolded proteins and alleviates SR stress, restored SR Ca2+signaling, BK and TRPM4 channel activity, prevented loss of myogenic tone, and reduced ICH. We conclude that alterations in SR Ca2+handling that impair membrane potential regulating ion channel activity result in dysregulation of SMC membrane potential and loss of myogenic tone contributing to age-related cSVD inCol4a1+/G1344Dmice.Graphical Abstract