The pericyte connectome: spatial precision of neurovascular coupling is driven by selective connectivity maps of pericytes and endothelial cells and is disrupted in diabetes

Abstract

Functional hyperemia, or the matching of blood flow with activity, directs oxygen and nutrients to regionally firing neurons. The mechanisms responsible for this spatial accuracy remain unclear but are critical for brain function and establish the diagnostic resolution of BOLD-fMRI. Here, we described a mosaic of pericytes, the vasomotor capillary cells in the living retina. We then tested whether this net of pericytes and surrounding neuroglia predicted a connectivity map in response to sensory stimuli. Surprisingly, we found that these connections were not only selective across cell types, but also highly asymmetric spatially. First, pericytes connected predominantly to other neighboring pericytes and endothelial cells, and less to arteriolar smooth muscle cells, and not to surrounding neurons or glia. Second, focal, but not global stimulation evoked a directional vasomotor response by strengthening connections along the feeding vascular branch. This activity required local NO signaling and occurred by means of direct coupling via gap junctions. By contrast, bath application of NO or diabetes, a common microvascular pathology, not only weakened the vascular signaling but also abolished its directionality. We conclude that the exclusivity of neurovascular interactions may thus establish spatial accuracy of blood delivery with the precision of the neuronal receptive field size, and is disrupted early in diabetes.

Of neurons and pericytes: The neuro-vascular approach to diabetic retinopathy

“…A decline in Cx43 expression during the early stages of DR parallels the reduction of propagative vasomotor activity in retinal capillaries (Ivanova et al, 2017). Early DR was further found to disrupt the functional connectivity of the 3D pericyte map, with significantly impaired cellular coupling, reduced vasomotor response and impaired blood flow, as well as a lack of directionality in the vasoactive response (Kovacs-Oller et al, 2020).…”

“…Physiological studies in the CNS have proposed a feedforward/feedback model (reviewed in Iadecola, 2017) where neuro-signaling molecules (NO, Ach) initiate a response, while metabolic by-products (CO 2 , adenosine and lactate) of neuronal activity result in a secondary signaling wave intending to adjust the vascular demand based on consumption. An anatomical correlate in the form of a precapillary sphincter was observed at the interface of the penetrating arteriole and first order capillary appear to link blood flow in capillaries to the arteriolar inflow (Kovacs-Oller et al, 2020), as described in the brain (Nakai et al, 1989;Grubb et al, 2020). Together with this precapillary sphincter, the low connectivity between ECs of the capillary and ECs of the feeding artery seem to provide a structural limitation to over-irrigation during functional hyperemia and suggests an anatomical segregation of functional neurovascular domains, as proposed in the brain (Rungta et al, 2018).…”

“…Their contractile processes ensheathe capillaries, promoting local vasomotor control while their complex connectivity provides the NVU with precise spatio-temporal signals of the source of neuronal activity (Kovacs-Oller et al, 2020). This initial response can spread along neighboring pericytes and ECs to control blood flow tens of micrometers away from the site of stimulation (Ivanova et al, 2017;Kovacs-Oller et al, 2020). The propagative nature of pericyte activity plays a critical role in both local network interactions and in signaling to regulate NVU retinal blood flow upstream in precapillary arterioles.…”

More than just summed neuronal activity: how multiple cell types shape the BOLD response

“…Vasodilation arising from neuronal activity local to the mid-capillary bed can be communicated to upstream vessels by a regenerating hyperpolarising current that is mediated by Kir2.1 channels [103] and propagated between endothelial cells via connexin-40 containing gap junctions [126], which couple more efficiently and preferentially towards upstream vessels during functional activation [127]. Activation of endothelial NMDA receptors and endothelial NOS (eNOS) can also evoke dilation in adjacent vascular mural cells [128,129].…”

“…BOLD signals can also be shaped by multiple factors that modulate endothelial propagation of vasodilation. In the retina, endothelial conduction is dramatically reduced by the vasoconstricting hormone angiotensin II [139], and facilitated by nitric oxide (NO) [127]. In the cortex, neurovascular coupling depends on arterial endothelial cell caveolae, which may be required to cluster the ion channels required for propagation [140].…”