Vascular endothelial dysfunction in vascular dementia: a mechanism-based approach with semaglutide

Vascular dementia (VaD) is the second most common type of dementia after Alzheimer’s disease (AD) and progresses on the basis of cerebrovascular pathology. Endothelial dysfunction emerging in the early stages, progressing through impaired cerebral blood flow, blood-brain barrier (BBB) damage, and neurovascular unit (NVU) dysfunction, forms the fundamental pathophysiological basis of cognitive decline [1]. These processes, along with chronic hypoperfusion and recurrent ischemic stress, trigger oxidative stress, neuroinflammation, glymphatic system dysfunction, and disruption of white matter integrity, leading over time to increased neuronal and oligodendrocyte damage and loss of connectivity in neural networks [2].

The high prevalence of VaD requires the development of new therapeutic approaches. The pathophysiological mechanism of the disease suggests that vascular and neurovascular integrity can be pharmacologically modulated. In this context, semaglutide, an incretin-based antidiabetic agent and glucagon-like peptide-1 (GLP-1) receptor agonist, is a promising candidate.

Semaglutide enhanced the integrity of the neurovascular unit (NVU) and the stability of the blood-brain barrier (BBB) by increasing astrocyte–vascular interaction at the cortical and hippocampal levels; this effect was also found to be associated with a reduction in capillary rarefaction at the microcirculatory level and suppression of leukocyte–endothelial interaction in cerebral postcapillary venules. Additionally, a significant improvement in the astrocyte covering around blood vessels was observed, and hippocampal neurodegenerative changes and structural damage were reduced [3]. These mechanisms suggest that semaglutide may be effective against neurovascular and microvascular dysfunction processes involved in the pathogenesis of VaD.

When considered as a model representing inflammatory endothelial activation, vascular damage, and cellular adhesion processes in the atherosclerotic vascular wall, it has been reported that semaglutide reduces the expression of VCAM -1 and ICAM-1—adhesion molecules expressed on endothelial cells that play a critical role in the adhesion of monocytes/macrophages to the vascular wall—are reduced by semaglutide, and that, in parallel, monocyte/macrophage adhesion and vascular inflammatory cell infiltration are suppressed [4]. These processes are considered to be associated with cerebral microvascular inflammation and endothelial dysfunction in the pathogenesis of VaD.

Vascular remodeling, characterized by intimal hyperplasia and medial thickening of the vessel wall, is a significant pathological process that contributes to reduced cerebral blood flow and microvascular dysfunction through smooth muscle cell proliferation and structural reorganization; it forms the structural basis of vascular damage associated with chronic hypoperfusion in the pathogenesis of VaD. It has been reported that semaglutide suppresses this pathological remodeling process by reducing intimal hyperplasia and medial thickening; this effect is thought to reflect a potential vasoprotective mechanism that could help limit the loss of vascular integrity and microcirculatory dysfunction observed in VaD [5].

These findings suggest that semaglutide may be a potential therapeutic candidate for preserving neurovascular integrity by targeting the pathways of endothelial dysfunction, NVU/BBB disruption, and vascular inflammation involved in the pathogenesis of VaD.

References

1. Wang, F., Cao, Y., Ma, L., Pei, H., Rausch, W. D., Li, H., 2018. Dysfunction of cerebrovascular endothelial cells: prelude to vascular dementia. Frontiers in aging neuroscience, 10, 376.
2. Yang, H. M., 2025. Vascular dementia: From pathophysiology to therapeutic frontiers. Journal of Clinical Medicine, 14(18), 6611.
3. Estato, V., Obadia, N., Chateaubriand, P. H., Figueiredo, V., Curty, M., Costa Silva, M., … & Caire de Castro Faria-Neto, H., 2025. Semaglutide restores astrocyte–vascular interactions and blood–brain barrier integrity in a model of diet-induced metabolic syndrome. Diabetology & Metabolic Syndrome, 17(1), 2.
4. Jensen, J. K., Binderup, T., Grandjean, C. E., Bentsen, S., Ripa, R. S., & Kjaer, A., 2022. Semaglutide reduces vascular inflammation investigated by PET in a rabbit model of advanced atherosclerosis. Atherosclerosis, 352, 88-95.
5. Jensen, D. M., Skovsted, G. F., Bonde, M. F. B., Bentzon, J. F., Rolin, B., Franck, G., … & Nyberg, M., 2022. Semaglutide treatment attenuates vessel remodelling in ApoE−/− mice following vascular injury and blood flow perturbation. Atherosclerosis plus, 49, 32-41.