The brain is a glutton for blood. Though it weighs less than 2 Kg, it sucks up a fifth of the oxygen we breathe and has a cerebrovascular system to match. It is no wonder that various insults to the blood vessels of the brain, including clogged and Aβ-laden arteries, may lead to dementia (see ARF related news story). But blockages are not the only cerebrovascular problem that compromises brain function. Overzealous vascular smooth muscle cells (VSMCs) can squeeze intracerebral and pia matter blood vessels, reducing cerebral blood flow. As Berislav Zlokovic and colleagues report in the January 10 PNAS online, such increased contractions are induced by serum response factor and myocardin, and these transcription factors are elevated in VSMCs from AD patients. The findings suggest that blood vessel contractility may be of pathological relevance in AD and other dementias.

Zlokovic and colleagues, at the University of Rochester School of Medicine, New York, first noted that expression of several VSMC-specific proteins is elevated in tissue taken from AD patients with severe pathology compared to control tissue samples. To test if more expression translates into more protein, first author Nienwen Chow and colleagues tested the samples by Western blot. They found that many proteins involved in vascular muscle contraction were elevated in AD, including myosin heavy chain, calponin, and α-actin. They also found that levels of serum response factor (SRF) and myocardin (MYOCD) were higher than normal; this might explain the abundance of the contractile proteins, since together the two transcription factors regulate a large number of VSMC genes.

What might these protein increases do to blood vessels? Chow and colleagues found that VSMCs isolated from AD patients were more contractile compared to those cells taken from control subjects. In response to potassium chloride, which induces muscle contraction, AD VSMCs shortened by about 25 percent, whereas normal smooth muscle cells only managed to shrink by about 9 percent. Similarly, transducing normal VSMCs with human MYOCD boosted levels of contractile proteins and strengthened contractility. In contrast, silencing SRF with interfering RNA had the opposite effect. The results suggest that increased expression of SRF and/or MYOCD could squeeze cerebral blood vessels and rob the brain of oxygen. In fact, that is what happened when the authors boosted MYOCD in mice.

Because knockouts of MYOCD and SRF are lethal, Chow used perfusion to transfect mouse sub-arachnoid pial arteries with a MYOCD expression gene. The authors then measured changes in cerebral blood flow induced by brain activation, in this case by tweaking the animal’s whiskers. In mice transfected with MYOCD, the blood flow increased only about half as much as seen in mice transfected with an inert construct. MYOCD had a similar effect in two different transgenic mouse models of AD, one expressing human amyloid precursor (APP) protein with the Dutch, Iowa, and Swedish mutations, and the other the APPSw+/- mouse. In both cases, whisker-stimulated blood flow dropped down to about half. Given the similar responses in wild-type and transgenic animals, it is unclear whether the AD-like pathology has any effect on blood vessel contraction in these animals. Aβ, for one, seems to have little effect on the smooth muscle because when Chow and colleagues challenged human cerebral VSMCs with various forms and concentrations of the peptide, SRF levels remained unchanged. Whether amyloid has a hand in this or not, the effects of SRF and MYOCD on VSMC contractility and the increased levels of those proteins in the human AD brain suggest that the role of vascular smooth muscle in the pathology of this and other dementias may be worthy of closer scrutiny.—Tom Fagan


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  1. This interesting study suggests a molecular mechanism that may explain how CAA contributes to dementia. Clinical studies have indicated that CAA contributes to the dementia in AD, and it has been apparent for decades that CAA eventually results in vascular smooth muscle death. This would obviously lead to dysregulation of cerebral blood flow, something that can't be good for brain function. The work of Chow, Zlokovic, and colleagues shows that serum response factor and myocardin are both upregulated in AD vascular smooth muscle cells, and that this may lead to vascular hypercontractility. This suggests that blood flow abnormalities in AD may exist prior to vascular smooth muscle cell death and that SRF/myocardin may represent new therapeutic targets for improving cerebral blood flow, and hence cognition, in AD. Furthermore, the data may have relevance for other forms of CAA, such as British, Danish, Dutch, and Icelandic.

    It is a little surprising that exogenously applied Aβ does not initiate the entire process. This leaves the initial stimulus for the SRF/myocardin overexpression unidentified. The authors suggest environmental (hypoxia) and genetic factors (gene polymorphisms) as initial hypotheses.

    View all comments by Thomas Beach
  2. The present paper by Chow et al. brings into sharp focus the significance of vascular factors in Alzheimer disease (AD). Age is a major risk factor for both AD and for cerebrovascular and cardiovascular disease. The most prominent pathology associated with vascular dementia, and with many cases of AD, is large and small cerebral infarcts. But, as highlighted by Chow et al., the role of cerebrovascular disease in dementia may go way beyond infarction. They suggest that elevated serum response factor (SRF) and myocardin activity in vascular smooth muscle cells in AD results in hypercontractility in small arteries in the brain. This would lead to hypoperfusion of the brain and to the neurovascular uncoupling and failure of autoregulation that is commonly seen in AD.

    In addition to infarction and hypoperfusion, there is a third aspect of cerebrovascular disease to consider. Age changes in cerebral arteries include arteriosclerosis and atherosclerosis, so that even in those arteries that lack atherosclerotic plaques there is often an increase in stiffness of the vessel walls with age due to deposition of collagen in the tunica media and in the subintima. This generalized stiffening (arteriosclerosis) may play a significant role in the failure of elimination of amyloid-β (Aβ) from the brain in the elderly and in AD. Interstitial fluid (ISF) [1] drains from the brain along the basement membranes between the smooth muscle cells in the tunica media of artery walls [2]; this effectively is the “lymphatic drainage” of the brain. Aβ also appears to drain from the brain along artery walls and is deposited in basement membranes between smooth muscle cells in the media as insoluble Aβ in the early stages of cerebral amyloid angiopathy [3,4]. Mathematical modeling suggests that reflection waves that follow pulse waves are the motive force that drives the drainage of interstitial fluid and Aβ out of the brain along artery walls in the reverse direction to the flow of blood in vessel lumina [5]. Stiffening of artery walls with age may reduce the amplitude of pulse and reflection waves, slow the drainage of interstitial fluid and Aβ, and result in the deposition of Aβ in artery walls [6,7]. Experimental cholinergic deafferentation of cortical arteries also results in the deposition of Aβ in their walls, suggesting that vessel tone is a factor in maintaining the elimination of Aβ [8].

    It seems that aging of cerebral blood vessels may deliver a double dose of pathology to the brain—hypoperfusion and dysregulation of cerebral blood flow on the one hand and failure of elimination of Aβ and ISF on the other. The relevance of the work by Chow et al. may, therefore, have greater significance for the pathogenesis of AD than is expressed in their paper.

    Using small cortical arteries from eight late-stage AD brains, five age-matched controls, and five young controls, Chow et al. showed that serum response factor (SRF) and myocardin are overexpressed in AD vascular smooth muscle cells, resulting in a hypercontractile smooth muscle phenotype that appears to reduce cerebral blood flow and decrease the cerebral blood flow response to brain activation. A number of other proteins that interfere with normal function are overexpressed in the AD vessels. The observations in human arteries were confirmed in transgenic mice with mutations in the human amyloid precursor (APP) gene. The action of SRF and myocardin appears to be independent of Aβ, but the effect of hypercontractility in cortical arteries upon drainage of ISF and Aβ is not known.

    The results in the paper by Chow et al. are very significant. Their observation that silencing the SRF gene reduces the hypercontractility of AD vascular smooth muscle cells suggests that SRF and myocardin may be suitable therapeutic targets for reducing artery dysfunction and hypoperfusion in AD. It would be interesting to speculate on whether the perivascular elimination of Aβ would also be improved if SRF and myocardin activity were reduced.


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    . Perivascular pathways for the clearance of interstitial fluid from the brain and the pathology of Alzheimer's disease. Neuropathol Appl Neurobiol 2005;31:218.

    . Cerebral amyloid angiopathy: amyloid beta accumulates in putative interstitial fluid drainage pathways in Alzheimer's disease. Am J Pathol. 1998 Sep;153(3):725-33. PubMed.

    . Capillary and arterial cerebral amyloid angiopathy in Alzheimer's disease: defining the perivascular route for the elimination of amyloid beta from the human brain. Neuropathol Appl Neurobiol. 2003 Apr;29(2):106-17. PubMed.

    . Mechanisms to explain the reverse perivascular transport of solutes out of the brain. J Theor Biol. 2006 Feb 21;238(4):962-74. PubMed.

    . Cerebrovascular disease is a major factor in the failure of elimination of Abeta from the aging human brain: implications for therapy of Alzheimer's disease. Ann N Y Acad Sci. 2002 Nov;977:162-8. PubMed.

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    View all comments by Roy Weller


News Citations

  1. Of Cabbages and Rings—AD and the Vasculature

Further Reading

Primary Papers

  1. . Serum response factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in Alzheimer's phenotype. Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):823-8. PubMed.