. Precapillary sphincters maintain perfusion in the cerebral cortex. Nat Commun. 2020 Jan 20;11(1):395. PubMed.


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  1. Cerebral blood flow (CBF) and the increase in CBF evoked by neuronal activity are reduced early in Alzheimer’s disease (AD) (Iturria-Medina et al., 2016), with the decrease in CBF exceeding 40 percent in affected areas (Asllani et al., 2008). In humans developing AD, and in an AD mouse model, contractile pericytes constrict cortical capillaries sufficiently to generate these CBF decreases (Nortley et al., 2019), and in the AD mouse model there is no change in arteriole or venule diameter implicating pericyte constriction as the main cause of the CBF decrease (Nortley et al., 2019). Two new papers, one (Grubb et al., 2020) from the Lauritzen group in Copenhagen and one (Chow et al., 2020) from the Gu group at Harvard, now report novel mechanisms for the control of CBF, which may have implications for our understanding of the CBF fall that occurs in AD.

    CBF can be regulated by vascular smooth muscle cells around arterioles, or by contractile pericytes on the first four branching orders of capillaries coming off an arteriole (Hall et al., 2014). The Lauritzen group now report (Grubb et al., 2020) a specialized structure—termed a sphincter—present on 28 percent of the first-order capillaries branching off cortical penetrating arterioles. The sphincter consists of a narrowed region of the capillary wrapped by an NG2-expressing contractile cell, which conventionally would be called a pericyte (although the paper is careful to avoid getting involved in the debate about the nomenclature of the contractile cells on capillaries) (Attwell et al., 2016). 

    The authors found that some of these contractile cells were weakly labelled by the Nissl dye NeuroTrace 500/525. This was previously reported to only label non-contractile pericytes (Damisah et al., 2017), but our own unpublished data confirm labelling by NeuroTrace 500/525 of a substantial proportion of α-smooth muscle actin expressing pericytes (which contracted in response to a thromboxane A2 analogue).

    The sphincter has a smaller diameter than the adjacent part of the first-order capillary. The authors propose that this allows the sphincter to more significantly reduce the blood pressure being applied to downstream capillaries, and indeed sphincters are found preferentially in the capillaries coming off the penetrating arteriole near the cortical surface where the blood pressure is higher. Conceivably, pericytes or endothelial cells on capillaries downstream of the sphincter-containing vessel may sense neuronal activity and send a signal back to the sphincter to alter blood flow (Longden et al., 2017). It will be exciting to determine whether, in AD, constriction of the pericytes forming the sphincters has a larger effect on CBF than constriction of contractile pericytes that are not forming sphincters, or whether the sphincter-fed vessels are relatively protected from constriction. Detailed computer modelling, based on reconstructions of the vascular topology (Blinder et al., 2013; Kirts et al., 2020) will probably be needed to assess this. 

    The Gu group paper (Chow et al., 2020) proposes a completely novel mechanism regulating neurovascular coupling, based on the effect of knocking out the protein caveolin-1 from the endothelial cells forming arteries. Caveolin-1 is present in the membranes of caveolae—indentations of the plasma membrane that have been variously proposed to play a role in mediating transcytosis, regulating endothelial cell Ca2+ signalling, sorting membrane proteins, regulating G protein coupled receptors, anchoring GPI-linked proteins, modulating eNOS activity, mechanosignalling, regulating inflammatory pathways, regulating Akt and Erk signalling, and controlling cell proliferation.

    Gu’s group had earlier shown that suppression of caveolae-mediated transcytosis in endothelial cells by the lipid transporter Mfsd2a plays a key role in establishing the blood-brain barrier (Andreone, 2018). Surprisingly, they now report that, although this is true for the endothelial cells forming capillaries, which contain few caveolae, there are a large number of caveolae in the endothelial cells forming arterioles. This suggests that the blood-brain barrier may be weaker for arterioles than for downstream capillaries.

    When caveolin-1 was knocked out in arterial endothelial cells, caveolae were suppressed in these endothelial cells, and the 15 percent dilation of arterioles normally evoked by neuronal activity was roughly halved (their Fig. 2c), suggesting a major role for caveolin-1 in regulating neurovascular coupling at the arteriole level. A 15 percent increase of arteriole diameter would be expected (by simplistic use of Poiseuille’s law) to evoke a 1.154 = 1.75-fold decrease in arteriole resistance, and hence a 75 percent increase in flow if arterioles constituted the only significant resistance in the cortical vasculature. (In fact, arterioles comprise only around one-seventh of the total vascular resistance from the pial end of a penetrating arteriole to the pial end of a venul (Blinder et al., 2013), so the predicted increase would in fact be much smaller).

    Intriguingly, however, the authors in fact documented a fourfold (300 percent) increase in downstream capillary blood flow (their Fig. 2d), indicating that most of the increase in blood flow evoked by neuronal activity is presumably generated by relaxation of contractile pericytes on downstream capillaries. This idea could be tested by measuring capillary diameters near pericytes. This raises the question of whether the change of neurovascular coupling that they see on deleting caveolin-1 is not, as one might expect, occurring at the arteriole smooth muscle adjacent to the endothelial cells where the caveolae are being suppressed, but somehow instead at downstream capillary pericytes.

    The paper does not provide mechanistic investigations of how deletion of caveolin-1 alters neurovascular coupling (other than showing it is independent of eNOS activity). Whether the effects observed occur at the arteriole smooth muscle level or the capillary pericyte level, it will be fascinating to determine whether the caveolae-mediated effect is a novel neurovascular coupling mechanism independent of previously known pathways, as has been previously suggested to exist (Hosford and Gourine, 2019)  or whether caveolin-1 deletion somehow modulates the properties of an already known pathway.

    The role of the caveolin-regulated pathway in disorders such as AD will also be of great interest, since the caveolin-1 KO mouse has already been proposed (Dudau et al., 2016) as a model of dementia, including AD, and there is debate about the effect of changes in the levels of caveolin 1-3 in AD (Gaudreault et al., 2004; van Helmond et al., 2007; Alsaqati et al., 2017). 


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    View all comments by David Attwell
  2. Grubb et al. provide an excellent structural and functional description analysis of the precapillary sphincters. They express alpha smooth-muscle actin and basement membrane proteins, and their main role appears to be in reducing the perfusion pressure in the capillaries. Apart from preventing cerebrovascular complications related to high blood pressure, the sphincters may have a role in smooth vasomotion and the motive force for drainage of interstitial fluid from the brain (Carare et al., 2020). 

    Chow et al. demonstrate the presence of caveolae on arterial endothelium. They are essential for neurovascular coupling, whereas caveolae on smooth-muscle cells are not necessary for neurovascular coupling. The major facilitator superfamily domain-containing 2a (Mfsd2a) protein is absent from the caveolae of arterial endothelium, while it is associated with the blood-brain barrier and repair after injury such as subarachnoid hemorrhage.

    It will be exciting to decipher the full molecular pathways involved in neurovascular coupling and dysregulation, as they could provide valuable therapeutic targets for stroke or subarachnoid hemorrhage.


    . Vasomotion Drives Periarterial Drainage of Aβ from the Brain. Neuron. 2020 Feb 5;105(3):400-401. PubMed.

    View all comments by Roxana Carare
  3. The two papers by Chow et al. and Grubb et al. significantly advance our understanding of neurovascular physiology and blood flow control.

    Through a combination of elegant in vivo two-photon imaging, molecular manipulations, pharmacology, and electron microscopy, Chow et al. report that neurovascular coupling is mediated by arteriolar endothelium to smooth muscle cell (SMC) interactions via an endothelial caveolae-dependent mechanism.

    They show that deletion of Caveolin 1 exclusively in endothelium markedly reduces the amplitude of vasodilation following whisker stimulation. Additional deletion of endothelial nitric oxide synthase (eNOS) almost completely abolished neurovascular coupling. Ectopic expression of MFSD2A, a molecule they previously identified as a suppressor of caveolae formation (Ben-Zvi et al., 2014), also attenuates NVC.

    There are several interesting conclusions from this study:

    1) The arteriolar endothelium appears to be a central hub through which all other signals (possibly neuronal or astrocytic) need to go to achieve vasomotility. In the absence of caveolae or endothelial eNOS, NVC coupling is essentially abolished.

    2) Caveolae are markedly enriched in arteriolar endothelium, but not in capillaries. This is consistent with the observation that the overlying smooth muscle cells (SMCs) but not capillary pericytes are the contractile cells that modulate NVC (Hill et al., 2015; Grutzendler and Nedergaard, 2019; Jun 2015 news). 

    3) Their observations are consistent with previous studies, mainly in the peripheral vasculature, showing that loss of Caveolins induces endothelial dysfunction and reduces myogenic tone, likely through loss of eNOS signaling (Lian et al., 2019). 

    4) Their results are complementary to recent work from the Nelson lab showing a role of endothelium in potassium sensing through inward-rectifier K+ (KIR2.1) channels to produce a rapidly propagating retrograde hyperpolarization that causes upstream arteriolar dilation (Longden et al., 2017). 

    5) Their demonstration of structural and functional regional endothelial differences is consistent with the differential transcriptome of arteriolar and capillary endothelial cells as well as the overlying SMCs and pericytes as observed by single-cell RNA seq analysis (Vanlandewijck et al., 2018) and the differential labeling with the uniquely pericyte-specific (completely excluded from SMCs) Neurotrace 500/525 dye which we previously described (Damisah et al., 2017). 

    In Grubb et al., the authors implement in vivo two-photon imaging in mice that express a fluorescent reporter in all mural cells (NG2-DsRed) while studying aspects of neurovascular coupling. They report the unexpected finding that in addition to the normal-looking, ring-like SMCs around brain arterioles (Hill et al., 2015), there is a small subpopulation of SMCs that have the appearance of a sphincter with greater degree of contractility, and which are located at the transition between the penetrating arteriole and first-order branches.

    They provide some evidence, mostly by modeling, that these sphincter-like SMCs generate the largest changes in resistance of all brain vessels and might be important for protecting vasculature and brain tissue from potentially adverse pressure changes.

    This study raises several questions:

    1) What is unique about these cells from a cellular and molecular point of view compared to the immediately adjacent SMCs?

    2) Are these sphincter-like properties stable over time, or are many of these branchpoint SMCs capable of hypercontractility under certain physiological or pathological circumstances?

    3) The authors demonstrate the hypercontractile features of these cells during spreading depolarization, potentially a critical finding in the context of ischemia, migraine, and microvascular occlusions.

    In summary, this paper adds significantly to our understanding of the structural and functional diversity of mural cells in the brain.


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    View all comments by Lei Tong

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