Defective Ca2+- dependent activation of TRPM4 channels 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), but the pathogenic mechanisms are largely unknown. Mice with a missense mutation in Col4a1 at 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. Treating Col4a1+/G1344D mice 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 in Col4a1+/G1344D mice. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/505186v3_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@11a8cb9org.highwire.dtl.DTLVardef@d00b8org.highwire.dtl.DTLVardef@1aa5b24org.highwire.dtl.DTLVardef@145a9c0_HPS_FORMAT_FIGEXP M_FIG C_FIG