. Interpericyte tunnelling nanotubes regulate neurovascular coupling. Nature. 2020 Aug 12; PubMed.


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  1. Neurovascular coupling by capillary inter-pericyte tunneling nanotubes—a new player in cerebrovascular physiology?

    Brain pericyte physiology is an emerging field that underlines how our understanding of brain cerebrovascular function, despite great progress, is limited. The field is still developing and the debate about whether capillary pericytes are contractile or not has been ongoing for more than 100 years (Krogh, 1919). The debate was reignited by a paper from Peppiatt et al. in 2006 that described contractile “bump-on-a-log” pericytes in brain slices. The debate has been muddied by a disagreement on mural cell nomenclature, where some scientists have moved away from the original definition set by Zimmermann and created their own terminology and named all mural cells that express α-smooth muscle actin (α-SMA) vascular smooth muscle cells (VSMC), while non-α-SMA expressing mural cells are termed pericytes (Hill et al., 2015). The point is that all non-spindle-shaped morphological mural cells on intraparenchymal arterioles and capillaries that are not true VSMCs should be named pericytes.  While the contractile ability of ensheathing pericytes on first- to fourth-order capillaries are now generally accepted (Grant et al., 2019; Cai et al., 2018; Grubb et al., 2020), the contractility of α-SMA-lacking true pericytes on fifth-plus-order capillaries is still a matter of debate (Hill et al., 2015; Hartmann et al., 2020; Alarcon-Martinez et al., 2019; Grutzendler and Nedergaard, 2019). A previous study by Alarcon-Martinez et al. showed that α-SMA may be lost during retinal fixation if actin depolymerization is not prevented (Alarcon-Martinez et al., 2018) and that this source of error may explain different views of pericyte function.

    This new Nature paper by Alarcon-Martinez et al. brings more wood to the fire (Alarcon-Martinez et al., 2020) by presenting a putatively new feature of neurovascular coupling—interpericyte tunneling nanotubes (IP-TNT). TNTs are nanometer-sized tubes that connect the cytoplasm of two distant cells (Korenkova et al., 2020). In their new paper, the authors use the term to describe pericyte processes that do not form cytoplasmic connections, but gap junction connections. IP-TNT’s previously have been described in isolated pericytes where they conveyed α-synuclein transfer from one cell to another by budding off a large vesicle from the end of the TNT as the cells moved apart (Dieriks et al., 2017). The lack of cytoplasmic connections between the pericytes may suggest that it is more accurate to call them “processes of bridging pericytes.” Bridging pericytes are described in the recent preprint by Hartmann et al., who reported that ablation of bridging pericytes dilate both the proximal and distal capillaries, which supports their claim that true pericytes exert a tonus on the capillaries (Hartmann et al., 2020). We have observed bridging pericytes in the whisker barrel cortex, but only in young adults (12-14 weeks), which may suggests that some of the pericyte processes represent a remnant of vascular pruning during development (Korn and Augustin, 2015). 

    Alarcon-Martinez et al. argue against the pruning idea by referring to (i) the lack of endothelial markers, (ii) α-SMA staining in the IP-TNT, (iii) presence of organelles and mitochondria, (iv) process stability, and (v) existence of intercellular Ca2+ waves. Furthermore, the paper reports IP-TNTs in 6-month-old mice. It would be interesting to develop a method that quantifies IP-TNTs and to examine whether the IP-TNT density changes with age, which is important because IP-TNTs are the morphological substrate for interpericyte calcium signals. A recent preprint by Glück et al. shows how VSMC and ensheathing pericytes synchronize Ca2+ fluctuations, but Ca2+ fluctuations of true pericytes are irregular (Glück et al., 2020), which makes it difficult to interpret the relevance of intercellular Ca2+ waves between pericytes in terms of neurovascular coupling. One could argue that for an intercellular Ca2+ wave between pericytes to be relevant for blood flow control, it would need to travel from the ensheathing pericytes at the first- to fourth-order capillaries, which are crucial for blood flow control in the microvessels, to the precapillary sphincter and the penetrating arteriole Grubb et al., 2020). Future studies will need to address these and other issues. However, Alarcon-Martinez and colleagues have now identified IP-TNT as a potential factor that we will need to take into account in further studies of cerebrovascular function and neurovascular coupling in health and disease.


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    View all comments by Søren Grubb
  2. I was really fascinated by this paper. The field has always been struck by the restricted nature of the increases in blood flow produced by neural activity. For example, if you mechanically stimulate a mouse whisker, only the arteriole that goes to that region of the barrel cortex dilates. How is that possible, when the capillary network is interconnected like the streets in downtown Boston? We didn’t have the right instruments to sort that out.

    Now, Alarcon-Martinez and colleagues report that when two pericytes in the retina are interconnected by a tunneling nanotube, one dilates its vessel and the other constricts in response to neural activity. Assuming this mechanism also operates in brain, that would provide a hemodynamic way to focalize the increase in flow into certain areas. This is fantastic in terms of introducing a new concept to explain how this highly interconnected capillary network could be regulated. Capillaries are the ultimate oxygenation machine in the brain, but their regulation has been underexplored. This paper puts the focus back on capillary hemodynamics.

    View all comments by Costantino Iadecola

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  1. Tunneling Nanotubes—How Pericytes Control Blood Flow