Pathophysiology of the neurovascular unit: disease cause or consequence?

Abstract

Pathophysiology of the neurovascular unit (NVU) is commonly seen in neurological diseases. The typical features of NVU pathophysiology include tissue hypoxia, inflammatory and angiogenic activation, as well as initiation of complex molecular interactions between cellular (brain endothelial cells, astroctyes, pericytes, inflammatory cells, and neurons) and acellular (basal lamina) components of the NVU, jointly resulting in increased blood-brain barrier permeability, brain edema, neurovascular uncoupling, and neuronal dysfunction and damage. The evidence of important role of the brain vascular compartment in disease pathogenesis has elicited the debate whether the primary vascular events may be a cause of the neurological disease, as opposed to a mere participant recruited by a primary neuronal origin of pathology? Whereas some hereditary and acquired cerebral angiopathies could be considered a primary cause of neurological symptoms of the disease, the epidemiological studies showing a high degree of comorbidity among vascular disease and dementias, including Alzheimer's disease, as well as migraine and epilepsy, suggested that primary vascular pathology may be etiological factor causing neuronal dysfunction or degeneration in these diseases. This review focuses on recent hypotheses and evidence, suggesting that pathophysiology of the NVU may be initiating trigger for neuronal pathology and subsequent neurological manifestations of the disease.

Figure 1

Neurovascular unit (NVU) reorganization in response to pathogenic stimulus. Highly structured multicellular anatomy of the NVU (shown in the upper right inset) undergoes profound changes in response to pathogenic stimulus, such as tissue hypoxia, schematically shown in the lower inset. The subsequent ‘sequence of events' leading to neuronal injury includes the expression and release of pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), by astrocytes and surrounding cells and upregulation of their receptors in brain endothelial cells, stimulating endothelial proliferation and migration with consequent disruption of tight junctions and increased blood–brain barrier (BBB) permeability. Release of metaloproteases by migrating endothelial cells and pericytes leads to proteolytic disruption of the basement membrane and additional release of pro-angiogenic breakdown products of the extracellular matrix. Accompanying influx of serum proteins and water through disrupted BBB results in vasogenic edema, which further disconnects cellular interactions within the NVU; toxic serum components cause astrocyte activation. Upregulation and secretion of inflammatory mediators from both activated astrocytes and endothelial cells stimulates the expression of adhesion molecules in endothelial cells and the recruitment of inflammatory cells into the brain. Reactive oxygen species and proteases released from leukocytes and activated perivascular cells cause oxidative injury to neurons. Secondary injury to neurons, if prolonged or repeated, could cause dissociation of neuronal projections from the NVU, uncoupling and subsequent retrograde degeneration. Some of the described events and their manifestation occur at specific sites of the brain microcirculatory tree: uncoupling at the level of arterioles, BBB disruption at the level of capillaries, and leukocyte recruitment at the level of postcapillary venules.

Figure 2

Cellular interactions implicated in the development, maturation and functional responses of the neurovascular unit (NVU). Current understanding places pericyte–endothelial cell interactions, mediated via canonical Wnt/β-catenin signaling, at the core of central nervous system (CNS)-specific vascular morphogenesis, the blood–brain barrier (BBB) specialization and maintenance during development. Whereas astrocytes provide trophic influence involved in inducing and maintaining BBB functions, their principal role is in establishing metabolic and functional link between endothelial and neuronal compartments, resulting in neurovascular coupling and local cerebral blood flow regulation. Pericytes contribute to the blood flow regulation by responding with contraction or relaxation to vascoactive stimuli released by surrounding cells.

Figure 3

Vascular hypothesis of neurodegeneration in Alzheimer's disease. Early triggers of homeostatic misbalance are common vascular risk factors, including age, hypertension, and cholesterol, leading to atherosclerotic disease and microvascular fibrosis. Functional consequence of these changes is chronic hypoperfusion that initiates neurovascular remodeling cascade. While the aberrant clearance of amyloid-β (Aβ) across the blood–brain barrier (BBB) initiates ‘seed' accumulation of Aβ in the brain and brain vessels, endothelial senescence, and impaired adaptive angiogenic response perpetuates chronic hypoxia, jointly leading to increased Aβ burden and clinical symptoms of mild cognitive impairment. Subsequent accelerated synapse loss and neurodegeneration in combination with progressive vascular pathology result in advanced cognitive loss characteristic of progressive disease.

Figure 4

Current understanding of amyloid-β (Aβ) transport across the blood–brain barrier (BBB). Soluble Aβ efflux from the brain across the BBB is mainly mediated by lipoprotein receptor-related protein 1 (LRP1); LRP1 expression declines in aging and Alzheimer's disease, leading to brain Aβ accumulation due to reduced clearance. Aβ complexes with ApoE and ApoJ could be eliminated from the brain via other LRP-family members, LRP8 and LRP2, respectively, but the capacity of these transporter systems and their age-dependent modulation is not known. Whereas a role for luminal P-glycoprotein (Pgp) in Aβ efflux has been proposed, molecular mechanisms and potential ‘collaboration' between LRP1 and Pgp remain uncertain. Aβ transported from the brain into circulation binds soluble LRP (sLRP) and is removed through liver degradation of the complex. Brain accumulation of Aβ could also result from increased influx of circulating Aβ; the principal receptor involved in this process is RAGE (receptor for advanced glycation). Aβ complexes with ApoJ could also be transported into the brain via LRP2 (gp330/Megalin), although the capacity of this route is significantly reduced due to receptor saturation by high circulating levels of ApoJ. Brain endothelial ABCG2 (BCRP) limits Aβ influx from peripheral compartment. Disturbed balance of Aβ influx and efflux across the BBB could be therapeutically targeted to reduce amyloid burden in the brain; for example, brain delivered anti-Aβ antibodies complex soluble brain Aβ; immunocomplexed Aβ is then eliminated by reversed transcytosis across the BBB via both LRP1 (recognizing Aβ-component of the complex), and via FcRn (recognizing Fc domain of the antibody)—later route becomes more important in aged animals, where vascular LRP1 expression declines with age.

Figure 5

Mechanisms involved in epileptogenesis triggered by the blood–brain barrier (BBB) permeability changes. Brain influx of serum proteins at sites of the BBB disruption, in particular that of albumin and thrombin, trigger profound astrocytic responses. Astrocytes internalize albumin via transforming growth factor (TGF)β receptors and this process triggers calcium-dependent signaling, leading to transcriptional changes; as a result, potassium inward rectifier, Kir4.1, and glutamate transporters are downregulated, whereas cytokines are upregulated and released by astrocytes. Consequently, synaptic buffering of potassium and glutamate is reduced, leading to increased excitability during neuronal activity and changed neuronal network responses leading to epileptogenesis.

Figure 6

Brain endothelial glycocalyx as a source of circulating biomarkers and therapeutic targets for neurovascular injury. Brain endothelial cell (BEC) glycocalyx is an exceptionally thick layer composed of sugar residues decorating glycolipids, membrane and adsorbed glycoproteins and proteoglycans that cover luminal lining of BECs and participate in essential functions of the neurovascular unit (NVU) (i.e., blood–brain barrier permeability, blood flow control, interactions with inflammatory and immune cells, as a source of adsorbed growth factors, thrombogenesis, and angiogenesis). Through the activation of membrane proteases by hypoxic or inflammatory stimuli, BEC glycocalyx components (proteins, glycosylated fragments of proteins, glycosylated lipids, oligosaccharides, etc.) are promptly ‘shed' into circulatory compartment, creating a pool of unique endothelial-derived biomarkers that could be used to assess NVU and brain pathology. Luminal BEC (glyco)proteins, such are for example adhesion molecules and transporters, are systemically accessible imaging and therapeutic targets for assessing and modifying functions of the NVU in disease.