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Serum response factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in

Nienwen Chow1, Robert D Bell, Rashid Deane

  • 1Socratech Research Laboratories L.L.C., Department of Neurosurgery, University of Rochester School of Medicine, 601 Elmwood Avenue, Rochester, NY 14642, USA.

Proceedings of the National Academy of Sciences of the United States of America
|January 12, 2007
PubMed

Insights

Alzheimer's disease (AD) involves cerebral blood flow (CBF) issues. Researchers found that high levels of serum response factor (SRF) and myocardin (MYOCD) in cerebral arteries cause hypercontractility and reduced CBF in AD.

Area of Science:

  • Neuroscience
  • Vascular Biology
  • Molecular Biology

Background:

  • Cerebral angiopathy and cerebral blood flow (CBF) dysregulation are implicated in Alzheimer's disease (AD) pathogenesis.
  • Vascular smooth muscle cells (VSMC) play a critical role in regulating CBF.

Purpose of the Study:

  • To investigate the role of transcription factors serum response factor (SRF) and myocardin (MYOCD) in VSMC dysfunction in AD.
  • To determine the impact of SRF-MYOCD pathway on cerebral artery hypercontractility and CBF regulation in AD models.

Main Methods:

  • Analysis of SRF and MYOCD expression in VSMC from AD patients.
  • Overexpression and silencing of MYOCD and SRF in human and mouse cerebral VSMC.
  • In vivo gene transfer of MYOCD and Srf silencing in mouse cerebral arteries.
  • Assessment of VSMC contractility, relaxation, and CBF responses in wild-type and AD model mice.

Main Results:

  • AD VSMC showed elevated SRF and MYOCD levels, leading to overexpression of contractile proteins and hypercontractility.
  • MYOCD overexpression induced an AD-like hypercontractile phenotype and impaired relaxation in control VSMC.
  • SRF silencing normalized contractile protein content and reversed hypercontractility in AD VSMC.
  • In vivo MYOCD transfer diminished CBF responses in wild-type and AD model mice, while Srf silencing improved them.
  • SRF expression was not altered by amyloid beta (Abeta) exposure in VSMC.

Conclusions:

  • SRF-MYOCD pathway activation in small cerebral arteries drives VSMC hypercontractility and CBF dysregulation in AD.
  • This pathogenic pathway appears to be initiated independently of Abeta.
  • Targeting the SRF-MYOCD pathway may offer a therapeutic strategy for AD-related cognitive decline.

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