16 January 2006. 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.
Chow N, Bell RD, Deane R, Streb JW, Chen J, Brooks A, Van Nostrand W, Miano JM, Zlokovic BV. Serum response factor and myocardin mediate arterial hypercontractility and cerebral blood flow dysregulation in Alzheimer’s phenotype. PNAS. January 16, 2007;104:823-828. Abstract