Thangwong Phakkawat, Tocharus Chainarong, Tocharus Jiraporn
Department of Medical Science, School of Medicine, Walailak University, Nakhon Si Thammarat, 80160, Thailand.
Research Center in Tropical Pathobiology, Walailak University, Nakhon Si Thammarat, 80160, Thailand.
Mol Neurobiol. 2025 Apr 9. doi: 10.1007/s12035-025-04914-5.
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.
慢性脑灌注不足（CCH）是认知障碍和痴呆尤其是血管性痴呆的关键指标。脑血流紊乱由于能量来源不足而改变神经元和胶质细胞的特性。缺氧诱导因子1α（HIF-1α）是一种转录因子，可响应低氧水平控制基因活性。它调节细胞适应的复杂网络，以改善缺氧情况下的氧合、代谢重编程和细胞存活。然而，最近的研究表明，HIF-1α不仅在神经保护中起作用，而且在脑损伤中也起作用。因此，充分理解这些疾病背后的机制至关重要。本综述强调了HIF-1α在CCH诱导的血管性痴呆（VaD）中的双重作用。最初，HIF-1α通过血管内皮生长因子（VEGF）信号促进血管生成来提供神经保护。然而，长期激活可能产生有害影响，包括氧化应激、神经炎症、血脑屏障功能障碍和认知障碍。有证据表明，HIF-1α通过PI3K/AKT/mTOR和MAPK/p-c-Jun信号等途径在急性缺血/缺氧诱导的VaD中发挥保护作用。然而，其在CCH慢性阶段的失调会导致认知下降和疾病进展。了解HIF-1α的复杂作用及其与其他分子途径的相互作用对于制定有效的治疗策略至关重要。因此，有必要对其参与这些病理过程进行深入的、有见地的讨论，因为HIF-1α对CCH诱导的VaD的确切作用仍有待确定，需要进一步研究。
