Serum response factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in Alzheimer's phenotype

doi:10.1073/pnas.0608251104

Serum response factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in Alzheimer's phenotype

*Socratech Research Laboratories L.L.C.,
^†Frank P. Smith Laboratories for Neuroscience and Neurosurgical Research, Department of Neurosurgery,
^‡Cardiovascular Research Institute, and
^§Functional Genomics Core, Arthur Kornberg Medical Research Building, University of Rochester School of Medicine, 601 Elmwood Avenue, Rochester, NY 14642; and
^¶Department of Medicine, Stony Brook University, Stony Brook, NY 11794

Edited by Eric N. Olson, University of Texas Southwestern Medical Center, Dallas, TX, and approved November 21, 2006 (received for review September 19, 2006)

Abstract

Cerebral angiopathy contributes to cognitive decline and dementia in Alzheimer's disease (AD) through cerebral blood flow (CBF) reductions and dysregulation. We report vascular smooth muscle cells (VSMC) in small pial and intracerebral arteries, which are critical for CBF regulation, express in AD high levels of serum response factor (SRF) and myocardin (MYOCD), two interacting transcription factors that orchestrate a VSMC-differentiated phenotype. Consistent with this finding, AD VSMC overexpressed several SRF-MYOCD-regulated contractile proteins and exhibited a hypercontractile phenotype. MYOCD overexpression in control human cerebral VSMC induced an AD-like hypercontractile phenotype and diminished both endothelial-dependent and -independent relaxation in the mouse aorta ex vivo. In contrast, silencing SRF normalized contractile protein content and reversed a hypercontractile phenotype in AD VSMC. MYOCD in vivo gene transfer to mouse pial arteries increased contractile protein content and diminished CBF responses produced by brain activation in wild-type mice and in two AD models, the Dutch/Iowa/Swedish triple mutant human amyloid β-peptide (Aβ)-precursor protein (APP)- expressing mice and APPsw ^+/− mice. Silencing Srf had the opposite effect. Expression of SRF did not change in VSMC subjected to Alzheimer's neurotoxin, Aβ. Thus, SRF-MYOCD overexpression in small cerebral arteries appears to initiate independently of Aβ a pathogenic pathway mediating arterial hypercontractility and CBF dysregulation, which are associated with Alzheimer's dementia.

Footnotes

^‖To whom correspondence should be addressed. E-mail: berislav_zlokovic{at}urmc.rochester.edu
Author contributions: N.C., R.D.B., R.D., and J.W.S. contributed equally to this work; J.M.M. and B.V.Z. designed research; N.C., R.D.B., R.D., J.W.S., J.C., and A.B. performed research; J.W.S. and W.V.N. contributed new reagents/analytic tools; N.C., R.D.B., R.D., J.W.S., A.B., J.M.M., and B.V.Z. analyzed data; and B.V.Z. wrote the paper.
Conflict of interest: B.V.Z. is the scientific founder of Socratech L.L.C., a startup biotechnology company with a mission to develop neuroprotective strategies in the aging brain and for brain disorders such as stroke, Alzheimer's disease, and other neurodegenerative disorders. All other authors declare no conflict of interest.
This article is a PNAS direct submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0608251104/DC1.
Abbreviations:

AD,

Alzheimer's disease;

CBF,

cerebral blood flow;

VSMC,

vascular smooth muscle cell;

SRF,

serum response factor;

MYOCD,

myocardin;

Aβ,

amyloid β-peptide.