Figure 1.

Schematic overview of proposed mechanism as one of the pathways leading to the development of WMLs in cSVD.

Chronic cardiovascular risk factors such as hypertension can lead to reduced blood flow and oxygen levels in poorly vascularized areas of the brain. Consequently, oxygen-sensitive oligodendrocyte precursor cells release VEGFA, mediated by Hif1/2a signaling, which triggers angiogenesis in an attempt to boost vascularization and improve oxygen supply. This process triggers increased BBB permeability by reducing tight junction proteins such as Claudin-5 and Occludin, which can lead to BBB leakages and neuroinflammation. Over time, the recurrence or accumulation of these events can result in brain tissue damage and the formation of white matter lesions, leading to clinical symptoms of cerebral small vessel disease (cSVD). Adapted from Manukjan et al. (2020). BBB: Blood–brain barrier; CBF: cerebral blood flow; Hif1/2a: hypoxia inducible factor 1/2a; O₂: oxygen; OPC: oligodendrocyte precursor cell; VEGFA: vascular endothelial growth factor A; WML: white matter lesion.