Acute Ablation of Cortical Pericytes Leads to Rapid Neurovascular Uncoupling

Abstract

Pericytes are perivascular mural cells that enwrap brain capillaries and maintain bloodbrain barrier (BBB) integrity. Most studies suggest that pericytes regulate cerebral blood flow (CBF) and oxygen delivery to activated brain structures, known as neurovascular coupling. While we have previously shown that congenital loss of pericytes leads over time to aberrant hemodynamic responses, the effects of acute global pericyte loss on neurovascular coupling have not been studied. To address this, we used our recently reported inducible pericyte-specific Cre mouse line crossed to iDTR mice carrying Cre-dependent human diphtheria toxin (DT) receptor, which upon DT treatment leads to acute pericyte ablation. As expected, DT led to rapid progressive loss of pericyte coverage of cortical capillaries up to 50% at 3 days post-DT, which correlated with approximately 50% reductions in stimulus-induced CBF responses measured with laser doppler flowmetry (LDF) and/or intrinsic optical signal (IOS) imaging. Endothelial response to acetylcholine, microvascular density, and neuronal evoked membrane potential responses remained, however, unchanged, as well as arteriolar smooth muscle cell (SMC) coverage and functional responses to adenosine, as we previously reported. Together, these data suggest that neurovascular uncoupling in this model is driven by pericyte loss, but not other vascular deficits or neuronal dysfunction. These results further support the role of pericytes in CBF regulation and may have implications for neurological conditions associated with rapid pericyte loss such as hypoperfusion and stroke, as well as conditions where the exact time course of global regional pericyte loss is less clear, such as Alzheimer's disease (AD) and other neurogenerative disorders.

Brain Microvascular Pericytes in Vascular Cognitive Impairment and Dementia

“…This view of CBF dynamics was revolutionized by the findings that capillary diameter also changes with neural activity (Peppiatt et al, 2006;Hall et al, 2014;Kisler et al, 2017b;Khennouf et al, 2018;Rungta et al, 2018) and ischemia (Yemisci et al, 2009;Hall et al, 2014). Furthermore, the loss of pericytes has been reported to lead to diminishing CBF in response to functional hyperemia in pericytes-deficient mice (Bell et al, 2010;Kisler et al, 2017bKisler et al, , 2020. However, Hill et al (2015) refuted that pericytes are involved in the regulation of CBF, and put forward the view that arteriolar SMCs may be the key players regulating CBF.…”

How Long Are Reperfusion Therapies Beneficial for Patients after Stroke Onset? Lessons from Lethal Ischemia Following Early Reperfusion in a Mouse Model of Stroke

“…In fact, mice deficient in pericytes had amyloid angiopathy and cerebral β-amyloidosis because of decreased clearance of soluble amyloid β, causing development of tau pathology and early neuronal loss, and resulting in cognitive dysfunction [ 71 ]. Further, pericyte deficiency causes decreased blood flow [ 47 , 72 , 73 ] and amyloid β oligomers constrict capillaries in AD through signaling to pericytes, thereby leading to CBF reduction [ 74 ]. In contrast, pericyte implantation enhanced CBF and reduced amyloid β deposition in a mouse model of AD [ 75 ].…”

A nuclear fluorescent dye identifies pericytes at the neurovascular unit

“…The presence of contractile machinery is consistent with pericyte function to actively modify their tone and modulate the capillary diameter and blood flow (CBF) (Kawamura et al, 2003;Peppiatt et al, 2006;Lacar et al, 2012;Hall et al, 2014;Mishra et al, 2016;Kisler, et al, 2017;Isasi et al, 2019;Nortley et al, 2019;Kisler et al, 2020;Nelson et al, 2020;Hartmann et al, 2020 Preprint;Ivanova et al, 2020 Preprint) although this role has not been established by some studies (Fernández-Klett et al, 2010;Hill et al, 2015;Wei et al, 2016). It is accepted that ensheathing pericytes from pre-capillary arterioles express α-SMA and regulate blood flow (Hill et al, 2015;Hartmann et al, 2020 Preprint) but the mechanisms underlying the contractility of mid-capillary pericytes involved in CBF regulation remain unknown.…”