Impaired intracellular Ca2+ signaling contributes to age-related cerebral small vessel disease in Col4a1 mutant mice

Humans and mice with mutations in COL4A1 and COL4A2 manifest hallmarks of
cerebral small vessel disease (cSVD). Mice with a missense mutation in
Col4a1 at amino acid 1344 (Col4a1+/G1344D) exhibit 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.  Treating
Col4a1+/G1344D mice with 4-phenylbutyrate, a compound that promotes the
trafficking of misfolded proteins and alleviates SR stress, restored
SR Ca2+ signaling and 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 in Col4a1+/G1344D mice.