Multifaceted role of nitric oxide in vascular dementia

Abstract

Vascular dementia is a highly heterogeneous neurodegenerative disorder induced by a variety of factors. Currently, there are no definitive treatments for the cognitive dysfunction associated with vascular dementia. However, early detection and preventive measures have proven effective in reducing the risk of onset and improving patient prognosis. Nitric oxide plays an integral role in various physiological and pathological processes within the central nervous system. In recent years, nitric oxide has been implicated in the regulation of synaptic plasticity and has emerged as a crucial factor in the pathophysiology of vascular dementia. At different stages of vascular dementia, nitric oxide levels and bioavailability undergo dynamic alterations, with a marked reduction in the later stages, which significantly contributes to the cognitive deficits associated with the disease. This review provides a comprehensive review of the emerging role of nitric oxide in the physiological and pathological processes underlying vascular dementia, focusing on its effects on synaptic dysfunction, neuroinflammation, oxidative stress, and blood‒brain barrier integrity. Furthermore, we suggest that targeting the nitric oxide soluble guanylate cyclase-cyclic guanosine monophosphate pathway through specific therapeutic strategies may offer a novel approach for treating vascular dementia, potentially improving both cognitive function and patient prognosis. The review contributes to a better understanding of the multifaceted role of nitric oxide in vascular dementia and to offering insights into future therapeutic interventions.

Keywords: apoptosis; blood‒brain barrier; cell death; dementia; mitochondrial dysfunction; neuroprotection; nitric oxide; nitric oxide synthase; oxidative stress; vascular dementia.

Figure 1

Historical milestones in the development of nitric oxide. Created with BioRender.com. NO: Nitric oxide.

Figure 2

Physiological role of nitric oxide. ① NO activates the sGC cGMP pathway to promote vascular smooth muscle cell relaxation. ② PINK1 accumulates on damaged mitochondrial membranes, and NO and peroxynitrite are formed by the binding of NO with superoxide ions produced by damaged mitochondria, regulating the activity of PINK1 and Parkin to promote autophagy in aging mitochondria and maintain cellular health. ③ Activation of macrophages by endotoxins leads to the production of inducible NOS, which interacts with arginine to produce NO. NO and peroxynitrite stimulate macrophages to further regulate immune responses and promote phagocytosis of endotoxins by macrophages. ④ NO has been demonstrated to bind and activate sGC in platelets, leading to a reduction in the expression levels of GP IIb/IIIa and a subsequent decrease in platelet adhesion to endothelial cells. ⑤ NO indirectly affects DNA stability and enhances cellular antioxidant, anti-inflammatory, and antiviral responses through the modulation of intracellular redox states and the regulation of various signaling pathways. ⑥ NO released from the postsynaptic compartment enters presynaptic terminals through the synaptic cleft, which further promotes the release of glutamate and affects the long-term enhancement of synapses by releasing retrograde signals.⑦ NO relaxes airway smooth muscle, dilates airways, and contributes to bacterial clearance in airway defense. ⑧ NO regulates various secretory functions, including gastric acid and pepsinogen production, by acting on parietal cells, chief cells, mucous cells, and gastrointestinal epithelial cells. Created with BioRender.com. Ca²⁺: Calcium ion; cGMP: cyclic guanosine monophosphate; GP IIb/IIIa: platelet glycoprotein IIb/IIIa complex; GTP: guanosine triphosphate; iNOS: inducible nitric oxide synthase; LTP: long-term potentiation; NMDAR: N-methyl-D-aspartate receptor receptor; NO: nitric oxide; NOS: nitric oxide synthase; Parkin: E3 ubiquitin ligase; PINK1: PTEN-induced kinase 1; PP1: protein phosphatase 1; ROS: reactive oxygen species; sGC: soluble guanylate cyclase; Zn²⁺: zinc ion.

Figure 3

Effects of different concentrations of NO on the endothelial function of cerebral blood vessels. In the context of VD, NO deficiency may lead to reduced synthesis of brain-derived neurotrophic factor, which inhibits the protective functions of astrocytes, ultimately resulting in BBB damage and the release of cytotoxic substances in the brain. Under pathological conditions, elevated NO concentrations may compromise the barrier function of vascular endothelial cells, increase permeability, and contribute to secondary brain edema. Created with Figdraw. BBB: Blood‒brain barrier; BDNF: brain-derived neurotrophic factor; NO: nitric oxide; VD: vascular dementia.

Figure 4

The modulatory effects of NO on metabolic processes under varying oxygen concentrations. In low-oxygen environments, the regional accumulation of NO within cells is critical for glycolysis, as NO helps maintain normal ATP levels by inhibiting mitochondrial respiration and enhancing glycolytic activity. Under conditions of elevated oxygen concentrations, hydroxyl radicals can interact with DNA constituents, leading to DNA damage and the generation of significant amounts of ROS within mitochondria. However, the capacity for DNA repair is limited, and the absence of histone protection renders mitochondrial DNA particularly vulnerable to ROS-induced damage. Furthermore, ROS can inflict DNA damage in endothelial cells, subsequently diminishing NO production. Created with Figdraw. ATP: Adenosine triphosphate; NO: nitric oxide; ROS: reactive oxygen species; TCA cycle: tricarboxylic acid cycle.

Figure 5

Role of NO in the modulation of synaptic plasticity in the context of VD. Created with Figdraw. cAMP: Cyclic adenosine monophosphate; cGMP: cyclic guanosine monophosphate; CREB: cAMP response element-binding protein; LTP: long-term potentiation; NMDA: N-methyl-D-aspartate; NO: nitric oxide; VD: vascular dementia.