The Bidirectional Role of Hypoxia-Inducible Factor 1 Alpha in Vascular Dementia Caused by Chronic Cerebral Hypoperfusion

Abstract

Chronic cerebral hypoperfusion (CCH) is a critical indicator of cognitive impairment and dementia, especially vascular dementia. Cerebral blood flow disturbance alters the properties of neurons and glial cells as a result of a deficit in energy sources. Hypoxia-inducible factor 1 alpha (HIF- 1α) is a transcription factor that controls gene activity in response to low oxygen levels. It regulates a complex network of cellular adaptations to improve oxygenation, metabolic reprogramming, and cell survival in hypoxic situations. However, recent research suggests that HIF- 1α plays a role not only in neuroprotection but also in brain injury. It is therefore critical to fully comprehend the mechanisms behind these disorders. This review highlights the dual role of HIF- 1α in CCH-induced VaD. Initially, HIF- 1α provides a neuroprotection by promoting angiogenesis through vascular endothelial growth factor (VEGF) signaling. However, prolonged activation can detrimentally effects, including oxidative stress, neuroinflammation, blood-brain barrier dysfunction, and cognitive impairment. Evidence suggests that HIF- 1α exerts its protective effects in acute ischemic/hypoxic-induced VaD through pathways such as PI3 K/AKT/mTOR and MAPK/p-c-Jun signaling. However, its dysregulation in chronic stages of CCH contributes to cognitive decline and disease progression. Understanding the complex role of HIF- 1α and its interactions with other molecular pathways is crucial for developing effective therapeutic strategies. Therefore, an informed, in-depth discussion of its involvement in these pathologic processes is necessary, as a precise contribution of HIF- 1α to CCH-induced VaD remains to be established and requires further investigation.

Keywords: Chronic cerebral hypoperfusion; Hypoxia-inducible factor 1 alpha; Neurodegeneration; Vascular dementia.