Dynamic connectivity maps of pericytes and endothelial cells mediate neurovascular coupling in health and disease

Abstract

21 22 Highlights 24 25  Within a structurally symmetric mosaic, pericytes form discriminatory connections 26 27  Pericyte connectome tunes with a precision matching a neuronal receptive field 28 29  Focal but not global input evokes a vasomotor response by strengthening the gap-junction 30 mediated signaling towards a feeding vascular branch 31 32  Disrupted functional connectivity map triggers loss of the functional hyperemia in diabetic 33 neuropathy 34 3 Summary 35 36Functional hyperemia, or matching blood flow to activity, is spatially accurate to direct the oxygen and 37 nutrients to regionally firing neurons. The underlying signaling mechanisms of neurovascular coupling 38 remain unclear, but are critical for brain function and establish the diagnostic power of BOLD-fMRI. 39Here, we described a mosaic of pericytes, the vasomotor capillary cells in the living retina. We then 40 tested if this symmetric net of pericytes and surrounding neuroglia predicted a connectivity map in 41 response to sensory stimuli. Surprisingly, we found that these connections were not only discriminatory 42 across cell types, but also highly asymmetric spatially. First, pericytes connected predominantly to other 43 neighboring pericytes and endothelial cells, and less to arteriolar smooth muscle cells, and not to 44 surrounding neurons or glia. Second, focal, but not global stimulation evoked a directional vasomotor 45 response by strengthening connections along the feeding vascular branch. This activity required local 46 NO signaling and occurred by means of direct coupling via gap-junctions. By contrast, bath application 47 of NO or diabetes, a common microvascular pathology, not only weakened the vascular signaling but 48 also abolished its directionality. We conclude that the discriminatory nature of neurovascular 49 interactions may thus establish spatial accuracy of blood delivery with the precision of the neuronal 50 receptive field size, and is disrupted early in microvascular disease. 51 52 53 56 57 Local changes in neural activity evoke a vascular response that is spatially restricted to the activated 58 region. The ubiquitous nature of the microvasculature and the diversity of routes through which blood 59 can be distributed make this task challenging. Furthermore, blood perfusion must be shifted or 60 expanded to accommodate for changing activity patterns. To accomplish changes in demand, 61 functional hyperemia must involve at least three events with a spatial precision that enables 62 discrimination of the active site from its resting neighbor: 1) sensing local changes, 2) transmission of 63 vasoactive signals along the supplying vascular branch, culminating in 3) vasomotor response that 64 directs blood to the active region. The mechanisms responsible for this spatial accuracy are not clear, 65 but are critical for brain function and establish the diagnostic power and precision of BOLD-fMRI 1 . 66 67The strategic location of capillaries within synaptic layers where neurotransmitters are released, 68 supports thei...

Imatinib Sets Pericyte Mosaic in the Retina

“…Finally, as we have recently shown, PCs form an essential 3D mosaic across the retina to provide a propagating vasomotor response in capillaries [22]. The signal for this propagation travels across gap junctions between neighboring PCs, thereby precisely supporting metabolic needs in the nervous tissue [6,7,22]. Any loss in this 3D PC structure contributes to the loss of this essential function.…”

“…In addition, PCs and smooth muscle cells (SMCs) express neural-glial marker-2 (NG2, or chondroitin sulfate proteoglycan 4 (Figure 1a). NG2 is a more suitable marker for PC morphological assessment and counting, as the somata of the cells are evenly visible and can be found in the inner retina in three separate layers [6,7,22] (Figure 1a,b and Figure 2). Imatinib has potentially been used as a selective cancer treatment, acting through multiple signaling pathways [23][24][25].…”

Imatinib Sets Pericyte Mosaic in the Retina

“…Finally, as we have recently shown, PCs form an essential 3D mosaic across the retina to provide a propagating contraction / dilation of capillaries. The signal for this propagation travels across gap junctions between neighboring PCs, thereby precisely supporting metabolic needs in the nervous tissue [22]. Any loss in this 3D PC structure contributes to the loss of this essential function.…”

“…1a-b). NG2 is a more suitable marker for pericyte morphological assessment and counting, as the somata of the cells are evenly visible [6,7,22] (Fig. 1a, 2).…”

Continued dysfunction of capillary pericytes promotes no-reflow after experimental strokein vivo

“…While the pathogenesis of no-reflow is multi-faceted, a critical step may involve constriction of cerebral microvessels by mural cells such as smooth muscle cells (SMCs) and capillary pericytes, which modulate hemodynamic resistance by controlling capillary diameter in response to neuronal activity [4][5][6][7][8][9][10][11][12] . Hybrid SMCs at the arteriole-to-capillary transition are reported to constrict and reduce blood flow to downstream capillaries after ischemia 13 , but 3 whether pericytes themselves have the potential to restrict blood flow within the capillary bed, the vascular territory where no-reflow occurs, remains contentious 14 .…”