Hill RA, Tong L, Yuan P, Murikinati S, Gupta S, Grutzendler J. Regional Blood Flow in the Normal and Ischemic Brain Is Controlled by Arteriolar Smooth Muscle Cell Contractility and Not by Capillary Pericytes. Neuron. 2015 Jun 23; PubMed.

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  1. This paper is based on observations gained from a combination of sophisticated and elegant methods using transgenic mice that express fluorescent markers in pericytes and smooth muscle cells, and built upon the previous work and expertise of Jaime Grutzendler in the design of such mice. The images showing the morphology of the cells associated with capillaries, arterioles, and venules are of exceptional quality. Traditionally, it was considered that NG2, smooth muscle actin (SMA), desmin, and platelet-derived growth factor-β were all markers for pericytes, but recent work has demonstrated that a variable amount of SMA is expressed by pericytes. The present study shows that SMA is not a valid marker for pericytes and they are not involved in active vasomotor responses as previously thought.

    Furthermore, transient middle cerebral artery occlusion resulted in vasoconstrictive responses exclusively from smooth muscle cells and not pericytes. These findings are highly significant for diseases associated with hypoperfusion of the brain and altered vasomotion, such as Alzheimer’s disease and cerebral amyloid angiopathy (CAA). One of the key pathogenic mechanisms of the development of CAA is the failure of perivascular lymphatic clearance of interstitial fluid and Aβ along the basement membranes of capillaries and arteries in the brain, as a result of biophysical changes associated with age-related stiffening of arterial walls. The present study opens up new methods and hypotheses involving the role of pericytes and smooth muscle cells in the pathogenesis of CAA.  

    View all comments by Roy Weller

  2. The images in this paper are beautiful. But the most remarkable thing about the paper is that, while it confirms earlier data by Hall et al., 2014, and Yemisci et al., 2009, showing that capillary pericytes regulate blood flow both physiologically and after stroke, it is written as if it does the opposite.

    This is because the authors use highly unconventional definitions of smooth muscle cell and of pericytes to reach their conclusions. Normally, vascular smooth muscle is defined as a layer of cells forming adjacent rings around arterioles (as in Figure 1A of the paper), while capillary pericytes have spatially isolated cell bodies looking like bumps on a log at roughly 30 micron intervals along capillaries. The authors, however, define a "pericyte" as a cell on a capillary that lacks smooth-muscle actin (a contractile protein) in processes around the vessel (for background information, pericytes have been known, since the work of Nehls and Drenckhahn, 1991, to show more actin expression when on microvessels near arterioles than when on vessels in the middle of the capillary bed). Any cell with a pericyte morphology that does have actin in circumferential processes they define to be a "smooth muscle cell," despite the vast difference in morphology of these actin-containing pericytes from true smooth muscle cells. Compare the green arteriole smooth muscle cells in Figure 1A with the cells indicated by arrowheads in Figure 1E; the latter are defined by the authors as "smooth muscle cells" despite the obvious similarity in appearance to the pericytes that are shown with arrows in Figure 1E. This inevitably leads to the erroneous conclusion that "pericytes" cannot regulate vessel diameter. 

    In fact, the data in this paper seem to be entirely consistent with the work of Hall et al. and Yemisci et al., who showed that capillary pericytes—the ones with actin—regulate cerebral blood flow both in health and in disease. Given the overall similarity of the results, despite the vocabulary used, it would be a pity if the field were to become dominated by arguments over cells' names. I hope, therefore, that people working in the field will rapidly resolve the issue of what to call these cells, so that the science and therapies based on it can be advanced.

    References:

    Hall CN, Reynell C, Gesslein B, Hamilton NB, Mishra A, Sutherland BA, O'Farrell FM, Buchan AM, Lauritzen M, Attwell D. Capillary pericytes regulate cerebral blood flow in health and disease. Nature. 2014 Apr 3;508(7494):55-60. Epub 2014 Mar 26 PubMed.

    Yemisci M, Gursoy-Ozdemir Y, Vural A, Can A, Topalkara K, Dalkara T. Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery. Nat Med. 2009 Sep;15(9):1031-7. Epub 2009 Aug 30 PubMed.

    Nehls V, Drenckhahn D. Heterogeneity of microvascular pericytes for smooth muscle type alpha-actin. J Cell Biol. 1991 Apr;113(1):147-54. PubMed.

    View all comments by David Attwell

  3. The study by Hill et al. is a beautiful illustration of how structure predicts function. As Dr. Attwell has pointed out, a primary controversy here is a difficulty in identifying cells that reside at the junction between arterioles and capillaries. We recently published an article that characterized mural cell morphologies at this junction, using the same inducible NG2-CreERTM driver line. In our study, however, we found mural cells, which would have been called either “precapillary arteriole smooth muscle cells” or “pericytes” by Hill et al., difficult to cleanly categorize into either group.

    Specifically, we found two types of cells that appeared to possess both characteristics of pericytes and smooth muscle cells. On the arteriole side of this junction, there were slightly elongated circumferential cells that expressed smooth muscle actin, just like smooth muscle cells. However these cells also exhibited ovoid, “bump on a log” somata more characteristic of classic pericytes (compare Fig. 4K of Hill et al. with Fig. 7f of ref (1)). On the capillary side of the junction, we found very elongated cells also with ovoid somata, but processes that formed a meshwork around the entire vessel lumen, unlike the thin stringy processes of pericytes deeper in the capillary bed. Interestingly, these cells expressed low levels of smooth muscle actin suggesting a possible role in control of vessel diameter (Fig 7h-k of ref (1)). Lacking an agreed-upon name for these cells, we called the former “smooth muscle-pericyte hybrid cells” and the latter a “mesh pericyte."

    With this cellular heterogeneity in mind, it is likely that some of the contractile cells called “pericytes” by Hall et al. (2) during in vivo studies and “precapillary arteriole smooth muscle cells” by Hill et al., were these cells of mixed phenotype. Future studies will need to zoom in on the function of mural cells at the arteriole-capillary junction, as they may be last gatekeepers for flow into the capillaries beds.

    References:

    (1) Hartmann et al. (2015), Neurophoton. 2(4), 041402. http://neurophotonics.spiedigitallibrary.org/article.aspx?articleid=2300459

    (2) Hall et al. (2014) Nature. 508(7494):55-60.

    View all comments by Andy Shih

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  1. Smooth Muscle Cells, Not Pericytes, Control Brain Blood Flow