Hypoxic oligodendrocyte precursor cell-derived VEGFA is associated with blood–brain barrier impairment

Abstract

Cerebral small vessel disease is characterised by decreased cerebral blood flow and blood–brain barrier impairments which play a key role in the development of white matter lesions. We hypothesised that cerebral hypoperfusion causes local hypoxia, affecting oligodendrocyte precursor cell—endothelial cell signalling leading to blood–brain barrier dysfunction as an early mechanism for the development of white matter lesions. Bilateral carotid artery stenosis was used as a mouse model for cerebral hypoperfusion. Pimonidazole, a hypoxic cell marker, was injected prior to humane sacrifice at day 7. Myelin content, vascular density, blood–brain barrier leakages, and hypoxic cell density were quantified. Primary mouse oligodendrocyte precursor cells were exposed to hypoxia and RNA sequencing was performed. Vegfa gene expression and protein secretion was examined in an oligodendrocyte precursor cell line exposed to hypoxia. Additionally, human blood plasma VEGFA levels were measured and correlated to blood–brain barrier permeability in normal-appearing white matter and white matter lesions of cerebral small vessel disease patients and controls. Cerebral blood flow was reduced in the stenosis mice, with an increase in hypoxic cell number and blood–brain barrier leakages in the cortical areas but no changes in myelin content or vascular density. Vegfa upregulation was identified in hypoxic oligodendrocyte precursor cells, which was mediated via Hif1α and Epas1. In humans, VEGFA plasma levels were increased in patients versus controls. VEGFA plasma levels were associated with increased blood–brain barrier permeability in normal appearing white matter of patients. Cerebral hypoperfusion mediates hypoxia induced VEGFA expression in oligodendrocyte precursor cells through Hif1α/Epas1 signalling. VEGFA could in turn increase BBB permeability. In humans, increased VEGFA plasma levels in cerebral small vessel disease patients were associated with increased blood–brain barrier permeability in the normal appearing white matter. Our results support a role of VEGFA expression in cerebral hypoperfusion as seen in cerebral small vessel disease.

β-asarone induces viability and angiogenesis and suppresses apoptosis of human vascular endothelial cells after ischemic stroke by upregulating vascular endothelial growth factor A

“…VEGFA can be tested in plentiful tissues in vivo under physiological conditions ( Braile et al, 2020 ; Bujaldon et al, 2019 ). Besides, VEGFA expression can be regulated by multiple factors, with hypoxia being the most crucial regulatory factor ( Manukjan et al, 2023 ). Several studies also demonstrated that VEGFA can participate in multiple pathophysiological processes, such as atherosclerosis, collateral circulation formation, increased vascular permeability, brain edema, neuroprotection, and nerve regeneration in ischemic cerebrovascular disease ( Manukjan et al, 2023 ; Neill et al, 2020 ; Parab et al, 2023 ).…”

The mRNA content of plasma extracellular vesicles provides a window into the brain during cerebral malaria disease progression

“…Taking our ndings together, we propose the following: that reduced microcirculatory ow resulting from parasite sequestration in the brain 46,47 results suboptimal brain perfusion [48][49][50] and neuronal hypofunction (evidenced by falling neuronal transcript levels), which is associated with progressive increase in glial cell activity 43 (evidenced by a progressive increase in glial transcripts), and other vascular-(VEGFA-VEGFR2 signalling [51][52][53][54][55][56][57] , platelet activation and coagulation 58 ), and neuronal-(neurotrophin signalling 59 , long-term potentiation 60 and glutamatergic signaling 61,62 ) related adaptive processes during late-stages of cerebral malaria, which may turn maladaptive and pathological 60,63 .…”

Effect of Clemastine on Neurophysiological Outcomes in an Ovine Model of Neonatal Hypoxic-Ischemic Encephalopathy

“…Most importantly, success of clemastine as a remyelination therapy has been noted in clinical trials of relapsing multiple sclerosis with chronic demyelinating optic neuropathy [22]. In HI, oligodendrocytes are particularly vulnerable to hypoxia and hypoglycemia [49]. Evidence suggests that in attempts to rescue demyelinated areas following a stroke, there is an increase in the density of perivascular oligodendrocyte progenitor cells [49].…”

“…In HI, oligodendrocytes are particularly vulnerable to hypoxia and hypoglycemia [49]. Evidence suggests that in attempts to rescue demyelinated areas following a stroke, there is an increase in the density of perivascular oligodendrocyte progenitor cells [49]. In term infants in particular, myelinated fibers are more metabolically active and hence more vulnerable to HI [50].…”