Extended Data Fig. 1: L-type voltage-gated Ca2+ channels and Ca2+-gated Cl− channels interact to control pericyte contraction. | Nature Neuroscience

Extended Data Fig. 1: L-type voltage-gated Ca2+ channels and Ca2+-gated Cl− channels interact to control pericyte contraction.

From: Inhibiting Ca2+ channels in Alzheimer’s disease model mice relaxes pericytes, improves cerebral blood flow and reduces immune cell stalling and hypoxia

Extended Data Fig. 1

a Anatomy of mural cells (defined by NG2-tdTomato label, recolored as below, in NG2-CreERT2-GCaMP5G-IRES-tdTomato mice) across the cerebral vasculature. SMCs form rings around pial arteries and penetrating arterioles (PAs, red image, red in schematic), pericytes of 1st-3rd branching order (green) from PAs wrap circumferential processes around capillaries, pericytes in the middle (orange) and on the venule side (purple, 1st-3rd branch order from venule, blue) of the capillary bed show more longitudinal and fewer circumferential processes (Supplementary Video 1). b Two-photon microscopy images (maximum intensity projections) of pericytes on 1st-3rd order capillary branches in acute cortical slices from wild-type NG2-CreERT2-GCaMP5G mice. Endothelin-1 (ET-1) was applied in the absence or presence of nimodipine (CaV blocker) and [Ca2+]i in pericyte somata (white dashed circles) and capillary diameter (white line) were measured. c Left: time course of ET-1 evoked [Ca2+]i rise in pericytes in the absence or presence of nimodipine or 10bm (TMEM16A blocker). Right: nimodipine or 10bm reduce the ET-1 evoked pericyte [Ca2+]i rise. P values from one-way ANOVA. d Nimodipine and 10bm reduce the ET-1 evoked capillary constriction at pericyte somata. P values from Kruskal−Wallis test. e Nimodipine reduces ET-1 evoked [Ca2+]i rise in SMCs. P value from unpaired t-test. f Incubation with vehicle used to dissolve nimodipine does not alter pericyte [Ca2+]i, but ET-1 applied in last 4 mins of recording raised [Ca2+]i, confirming pericytes remain responsive to ET-1 during prolonged imaging. P value from unpaired t-test. g Proposed mechanism of ET-1 evoked pericyte contraction (see also refs. 14,79): ET-1 evoked Ca2+ release from stores activates TMEM16A Ca2+-gated Cl− channels. The resulting Cl− efflux depolarises the pericyte, which promotes Ca2+ entry via CaVs, activating myosin-light chain kinase (MLCK) and pericyte contraction. h-i In awake head fixed mature WT mice, imaging (h) revealed that nimodipine (220 μg/kg i.v.) dilates arterioles/arteries, and capillaries (i). P values from unpaired t-tests. P-values are 2-tailed. Error bars are s.e.m.

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