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. 2007 Jan 16;104(3):823-8.
doi: 10.1073/pnas.0608251104. Epub 2007 Jan 10.

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

Nienwen Chow  1 , Robert D Bell, Rashid Deane, Jeffrey W Streb, Jiyuan Chen, Andrew Brooks, William Van Nostrand, Joseph M Miano, Berislav V Zlokovic
Affiliations

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

Nienwen Chow et al. Proc Natl Acad Sci U S A. .

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 beta-peptide (Abeta)-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, Abeta. Thus, SRF-MYOCD overexpression in small cerebral arteries appears to initiate independently of Abeta a pathogenic pathway mediating arterial hypercontractility and CBF dysregulation, which are associated with Alzheimer's dementia.

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Conflict of interest statement

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.

Figures

Fig. 1.
Fig. 1.
SRF/MYOCD and contractile protein expression in Alzheimer's cerebral VSMC. (a) Shown are Western blots of a full length SRF, SM α-actin, SM22α, and SM calponin (Upper) and of smooth muscle myosin heavy chain (SM MHC) and MYOCD (Lower) in AD and age-matched control VSMC. (b and c) Relative levels of expression of VSMC contractile proteins (b) and SRF (c) in AD (open bars) and controls (filled bars). (d) Relative levels of expression of MYOCD (Left) and quantitative RT-PCR for MYOCD mRNA (Right) in VSMC in AD (open bars) and controls (filled bars). Mean ± SEM from five to eight independent cultures per group. P, statistically significant difference between AD vs. controls.
Fig. 2.
Fig. 2.
VSMC contractility in response to KCl. (a) Cerebral control VSMC before (control), during (contraction), and after (relaxation) stimulation with KCl. (b) Contractility of AD VSMC vs. control VSMC after KCl stimulation. Mean ± SEM are from eight AD and five age-matched independent cultures. P, statistically significant difference. (c and d) Western blot analysis for SRF, SM α-actin, SM calponin, and SM MHC (c) and VSMC contractility after stimulation with KCl in MYOCD- (Ad.MYOCD) (filled bars) or Ad.GFP-transduced (control) age-matched VSMC (open bars) (d). (e) Western blots for SRF and SM calponin and (f) VSMC contractility after KCl stimulation in AD VSMC transduced with Ad.shSRF (filled bars) or control Ad.shGFP (open bars). Western blots in c and e are typical representatives of five independent experiments from five different cultures per group. In d and f, the maximal cell shortening was determined from 100 cells per culture in triplicates from three independent cultures per group (mean ± SEM); P, statistically significant difference between MYOCD- vs. GFP-transduced VSMC and sh.SRF- vs. sh.GFP-transduced AD VSMC, respectively, determined by Student's t test.
Fig. 3.
Fig. 3.
SRF/MYOCD regulate contractile phenotype in mouse aortic rings. Cumulative dose–response curves for acetylcholine (a), phenylephrine (b), and sodium nitroprusside (c) in mouse aortic rings transduced with Ad.MYOCD (solid circle) or Ad.GFP (open circle). Mean ± SEM from three rings per group; ∗, P < 0.05, MYOCD- vs. GFP-transduced by Student's t test.
Fig. 4.
Fig. 4.
MYOCD and sh.SRF gene transfer to mouse pial arteries alters CBF responses to vibrissal stimulation. (a) Expression of GFP in cerebral pial vessels after subarachnoid infusion of Ad.GFP. (Scale bar, 50 μm.) (b) PCR for MYOCD mRNA in cerebral pial vessels after in vivo transduction with Ad.MYOCD. (c) Increase in contractile protein content in cerebral pial arteries after MYOCD gene transfer compared with GFP controls by Western blot analysis. (d–f) Effect of MYOCD gene transfer on CBF increase after whisker stimulation compared with GFP controls in wild-type (d), Dutch/Iowa/Swe (e), and APPsw+/− mice (f). In d–f, mock colony-stimulating-factor controls (vehicle) were also studied. Mean ± SEM from five animals per group.
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