Abstract
Neurovascular coupling is a crucial mechanism that matches the high energy demand of the brain with a supply of energy substrates from the blood. Signaling within the neurovascular unit is responsible for activity-dependent changes in cerebral blood flow. The strength and reliability of neurovascular coupling form the basis of non-invasive human neuroimaging techniques, including blood oxygen level dependent (BOLD) functional magnetic resonance imaging. Interestingly, BOLD signals are negative in infants, indicating a mismatch between metabolism and blood flow upon neural activation; this response is the opposite of that observed in healthy adults where activity evokes a large oversupply of blood flow. Negative neurovascular coupling has also been observed in rodents at early postnatal stages, further implying that this is a process that matures during development. This rationale is consistent with the morphological maturation of the neurovascular unit, which occurs over a similar time frame. While neurons differentiate before birth, astrocytes differentiate postnatally in rodents and the maturation of their complex morphology during the first few weeks of life links them with synapses and the vasculature. The vascular network is also incomplete in neonates and matures in parallel with astrocytes. Here, we review the timeline of the structural maturation of the neurovascular unit with special emphasis on astrocytes and the vascular tree and what it implies for functional maturation of neurovascular coupling. We also discuss similarities between immature astrocytes during development and reactive astrocytes in disease, which are relevant to neurovascular coupling. Finally, we close by pointing out current gaps in knowledge that must be addressed to fully elucidate the mechanisms underlying neurovascular coupling maturation, with the expectation that this may also clarify astrocyte-dependent mechanisms of cerebrovascular impairment in neurodegenerative conditions in which reduced or negative neurovascular coupling is noted, such as stroke and Alzheimer’s disease.
Highlights
We review the timeline of the structural maturation of the neurovascular unit with special emphasis on astrocytes and the vascular tree and what it implies for functional maturation of neurovascular coupling
We introduce the components of the neurovascular unit (NVU), briefly summarize known signaling mechanisms that mediate neurovascular coupling (NVC), describe the changes that occur in NVC and NVU components during development and during neurological disorders, and end by suggesting future research directions to elucidate the mechanisms that underpin these NVC changes
A comprehensive understanding of how NVC is regulated during development and neurological disorders will improve our understanding of these biologically important processes, but potentially guide new therapeutic interventions in disease conditions characterized by cerebrovascular dysfunction
Summary
The brain is an energy-hungry organ; it comprises only 2% of body weight but uses about 20% of the body’s resting energy (Attwell and Laughlin, 2001; Howarth et al, 2012). Microglia, and blood vessels, and their communication at each of these interfaces influences how the NVU responds to neural activity to induce NVC and mediate changes in CBF (Attwell et al, 2010). During vascular infiltration into the brain, the basal lamina of blood vessels and the astrocyte-secreted basal lamina of the brain merge to form an interconnected cerebrovascular basal lamina, to which both the vessels and the astrocyte endfeet are anchored (Figure 2; Marin-Padilla, 2012) This anchoring gives rise to the close physical relationship between these important NVU components and enables their concerted functions in BBB maintenance and NVC regulation. This mechanism allows propagation of vascular responses up- and down-stream of the vasculature to mount a coordinated response to increase local CBF within a capillary network (Segal and Duling, 1986; Rungta et al, 2018; Kovacs-Oller et al, 2020)
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