Microglia modulate blood flow, neurovascular coupling, and hypoperfusion via purinergic actions

Abstract

Microglia, the main immunocompetent cells of the brain, regulate neuronal function, but their contribution to cerebral blood flow (CBF) regulation has remained elusive. Here, we identify microglia as important modulators of CBF both under physiological conditions and during hypoperfusion. Microglia establish direct, dynamic purinergic contacts with cells in the neurovascular unit that shape CBF in both mice and humans. Surprisingly, the absence of microglia or blockade of microglial P2Y12 receptor (P2Y12R) substantially impairs neurovascular coupling in mice, which is reiterated by chemogenetically induced microglial dysfunction associated with impaired ATP sensitivity. Hypercapnia induces rapid microglial calcium changes, P2Y12R-mediated formation of perivascular phylopodia, and microglial adenosine production, while depletion of microglia reduces brain pH and impairs hypercapnia-induced vasodilation. Microglial actions modulate vascular cyclic GMP levels but are partially independent of nitric oxide. Finally, microglial dysfunction markedly impairs P2Y12R-mediated cerebrovascular adaptation to common carotid artery occlusion resulting in hypoperfusion. Thus, our data reveal a previously unrecognized role for microglia in CBF regulation, with broad implications for common neurological diseases.

Immune–vascular mural cell interactions: consequences for immune cell trafficking, cerebral blood flow, and the blood–brain barrier

“… 119 This is consistent with pharmacological microglial depletion increasing capillary diameter and CBF. 119 Others, however, did not detect changes in CBF upon microglial depletion, 120 possibly reflecting differences in anaesthetics used or brain regions imaged. Conceivably, CBF changes in or PANX1 deficient mice may also be evoked by reductions in platelet aggregation in these mice.…”

“… 154 In contrast, blockade increases infarct size and microglial elimination reduces CBF after experimental stroke in murine models. 39 , 120 Microglial depletion, knock-out, or pharmacological blockade in mice also reduce neuronally evoked increases in CBF by , 120 suggesting that microglia may contribute to neurovascular coupling (NVC). Importantly, expression is reduced in various neurological diseases as shown in humans in AD and MS and in murine models of ischemic stroke, 155 – 157 which may therefore alter microglia-capillary interactions 132 , 135 , 158 and impair NVC 159 – 161 in these diseases.…”

“… 118 for a historical overview), microglia are beginning to be recognized as an important modulator of microvascular blood flow in the healthy and diseased adult CNS. 5 , 119 – 121 Peripheral immune cells and microglia generate peptides, purines, catecholamines, cytokines, chemokines, and reactive oxygen species (ROS) with established vasoactive properties. These soluble molecules modulate CBF, whether released locally from microglia or invading immune cells, from the perivascular space, 122 or into the circulation from distal tissues such as the gut.…”

“… 134 stimulation mediates integrin activation in microglial processes required for chemotaxis toward sites of ATP/ADP released from capillaries, as occurs when brain injury releases ATP from damaged cells and raises . 139 – 141 Interestingly, microglial processes contact 83% of pericytes on capillaries, and cover 15% of the EC surface, predominantly at sites of mitochondria, 120 which provide ATP released via capillary pannexin 1 (PANX1). 119 High levels of at the bulbous tips of microglial processes likely facilitate these contacts.…”

“… 142 Furthermore, 30% of all microglia somata are closely associated with capillaries. 119 Microglia also contact capillary segments where astrocyte endfeet are absent, forming an integral part of the glia limitans, 120 , 143 – 145 and so are ideally placed to modulate CBF.…”