Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain

Abstract

Pericytes are perivascular mural cells of brain capillaries that are positioned centrally within the neurovascular unit between endothelial cells, astrocytes and neurons. This unique position allows them to play a major role in regulating key neurovascular functions of the brain. The role of pericytes in the regulation of cerebral blood flow (CBF) and neurovascular coupling remains, however, debatable. Using loss-of-function pericyte-deficient mice, here we show that pericyte degeneration diminishes global and individual capillary CBF responses to neuronal stimulus resulting in neurovascular uncoupling, reduced oxygen supply to brain and metabolic stress. We show that these neurovascular deficits lead over time to impaired neuronal excitability and neurodegenerative changes. Thus, pericyte degeneration as seen in neurological disorders such as Alzheimer’s disease may contribute to neurovascular dysfunction and neurodegeneration associated with human disease.

RETRACTED ARTICLE: Pericyte degeneration causes white matter dysfunction in the mouse central nervous system

“…Because previous studies in mice with deficient PDGFRβ signaling did not find the effect of gender on pericyte coverage, BBB integrity or blood flow regulation 17,22,30,32 both male and female mice at 2, 4-6, 12-16, and 36-48 weeks of age were used in the study. To determine the role for fibrinogen in F7/F7 mice we carried out pharmacological studies with ancrod and tranexamic acid (TXA) and genetic studies using fibrinogen-deficient and plasminogen-deficient mice, as described below.…”

“…Pericytes control microvascular functions in neuron-dense grey matter regions including blood-brain barrier (BBB) permeability 15–17 and cerebral blood flow 18–22 . They die in AD 10,23–26 mild dementia 27 , stroke 19,20 and cerebral autosomal dominant arteriopathy with subcortical infarcts (CADASIL), the most common genetic ischemic small vessel disease associated with cognitive impairment 28 .…”

Dynamic Remodeling of Pericytes In Vivo Maintains Capillary Coverage in the Adult Mouse Brain

“…Pericyte-endothelial contact is critical for many vascular homeostatic functions, and it remains to be seen how modulation of pericyte structural plasticity on a broad level affects cerebral blood flow regulation, metabolite exchange, BBB integrity, and microvascular architecture. Whether capillary pericytes are involved in cerebral blood flow regulation is controversial (Attwell et al, 2015; Hill et al, 2015; Kisler et al, 2017). Our data suggests that pericyte loss leads to capillary dilation under basal conditions, which may decrease capillary flow resistance and alter metabolic exchange.…”

Mechanisms Mediating Functional Hyperemia in the Brain

“…A recent study in pericyte-deficient mice reported a reduction in functional hyperemia, a lowering of brain O 2 levels, and a loss of neurons in older animals (Kisler and others 2017). Although a reduction in capillary density was observed in these animals, which could have effects on the brain not directly related to the functional hyperemia response, the results indicate that functional hyperemia is important in maintaining neuronal health.…”

“…Existing computational analyses must be complemented by physiological experiments assessing the effect of capillary dilation on blood flow. Targeting capillary pericytes will be useful in answering this question (Kisler and others 2017). …”