| First Author | Yamasaki E | Year | 2023 |
| Journal | Proc Natl Acad Sci U S A | Volume | 120 |
| Issue | 5 | Pages | e2217327120 |
| PubMed ID | 36693102 | Mgi Jnum | J:344631 |
| Mgi Id | MGI:7439028 | Doi | 10.1073/pnas.2217327120 |
| Citation | Yamasaki E, et al. (2023) Faulty TRPM4 channels underlie age-dependent cerebral vascular dysfunction in Gould syndrome. Proc Natl Acad Sci U S A 120(5):e2217327120 |
| abstractText | Gould syndrome is a rare multisystem disorder resulting from autosomal dominant mutations in the collagen-encoding genes COL4A1 and COL4A2. Human patients and Col4a1 mutant mice display brain pathology that typifies cerebral small vessel diseases (cSVDs), including white matter hyperintensities, dilated perivascular spaces, lacunar infarcts, microbleeds, and spontaneous intracerebral hemorrhage. The underlying pathogenic mechanisms are unknown. Using the Col4a1(+/G394V) mouse model, we found that vasoconstriction in response to internal pressure-the vascular myogenic response-is blunted in cerebral arteries from middle-aged (12 mo old) but not young adult (3 mo old) animals, revealing age-dependent cerebral vascular dysfunction. The defect in the myogenic response was associated with a significant decrease in depolarizing cation currents conducted by TRPM4 (transient receptor potential melastatin 4) channels in native cerebral artery smooth muscle cells (SMCs) isolated from mutant mice. The minor membrane phospholipid phosphatidylinositol 4,5 bisphosphate (PIP(2)) is necessary for TRPM4 activity. Dialyzing SMCs with PIP(2) and selective blockade of phosphoinositide 3-kinase (PI3K), an enzyme that converts PIP(2) to phosphatidylinositol (3, 4, 5)-trisphosphate (PIP(3)), restored TRPM4 currents. Acute inhibition of PI3K activity and blockade of transforming growth factor-beta (TGF-beta) receptors also rescued the myogenic response, suggesting that hyperactivity of TGF-beta signaling pathways stimulates PI3K to deplete PIP(2) and impair TRPM4 channels. We conclude that age-related cerebral vascular dysfunction in Col4a1(+/G394V) mice is caused by the loss of depolarizing TRPM4 currents due to PIP(2) depletion, revealing an age-dependent mechanism of cSVD. |
