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Pharmacology & Chemical Biology Seminar Series
3/21/2024 - 12:00 PM-1:00 PM
“Position-dependent mechanistic heterogeneity in age-dependent cerebral small vessel disease associated with Col4a1 mutations.”

Scott Earley, PhD 
Professor of Pharmacology
University of Nevada
Reno School of Medicine

Humans and mice with mutations in the genes encoding the essential basement membrane protein type IV collagen (COL4A1 and COL4A2) manifest hallmarks of cerebral small vessel disease (cSVD), including white matter hyperintensities, dilated perivascular spaces, lacunar infarcts, microbleeds, and intracerebral hemorrhages. Our recent studies using mice with Col4a1 mutations in different positions have revealed striking mechanistic heterogeneity in the disease process. Age-dependent cerebral vascular dysfunction in mice with a glycine to valine substitution at position 394 (Col4a1+/G394V) is caused by the loss of depolarizing TRPM4 (transient receptor potential melastatin 4) currents in smooth muscle cells and inwardly rectifying K+ (KIR) channel activity in endothelial cells due depletion of PIP2, a co-factor required by channels. Blocking PI3 kinase to prevent the conversion of PIP2 to PIP3 repaired the defects in TRPM4 and KIR channel activity and restored vascular function. Cerebral vascular disease in 12-month-old mice with a Col4a1 mutation at 1344 (Col4a1+/G1344D) was linked to impaired sarcoplasmic regimen (SR) dependent Ca2+ signaling in smooth muscle cells. As these mice aged, they became more susceptible to intracerebral hemorrhaging and showed defects in TRPM4 and large-conductance Ca2+ activated K+ (BK) channel signaling in smooth muscle cells. Alleviating SR stress caused by the accumulation of misfolded collagen with a small molecule chaperone attenuated intracerebral hemorrhages and restored SR Ca2+ signaling and vascular function, suggesting that perturbations in SR function induced by misfolded proteins may underlie some types of cerebral blood vessel diseases. Our findings underscore the striking pathogenic diversity inherent in cSVDs.
  
 
Thomas E. Starzl Biomedical Science Tower
1395 Conference Room
200 Lothrop St
Pittsburgh, PA 15213
Contact
Melanie Hoffner

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