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.

No abstract

Pericytes are positioned between brain capillary endothelial cells, astrocytes and neurons. They degenerate in multiple neurological disorders. However, their role in the pathogenesis of these disorders remains debatable. Here, we generated an inducible pericyte-specific Cre line and crossed pericyte-specific Cre mice with iDTR mice carrying Cre-dependent human diphtheria toxin receptor (DTR). After pericyte ablation with diphtheria toxin, mice developed an acute blood-brain barrier (BBB) breakdown, severe loss of blood flow, and a rapid neuron loss associated with loss of pericyte-derived pleiotrophin (PTN), a neurotrophic growth factor. Intracerebroventricular PTN infusions prevented neuron loss in pericyte-ablated mice despite persistent circulatory changes. Silencing pericyte-derived Ptn rendered neurons vulnerable to ischemic and excitotoxic injury. Our data demonstrate a rapid neurodegeneration cascade linking pericyte loss to acute circulatory collapse and loss of PTN neurotrophic support. These findings could have implications for the pathogenesis and treatment of neurological disorders associated with pericyte loss and/or neurovascular dysfunction.