Vasoactive Neuropeptide Dysregulation: A Novel Mechanism of Microvascular Dysfunction in Vascular Cognitive Impairment

Abstract

INTRODUCTIONNeuropeptide dysregulation and microvascular injury are involved in pathogenesis of vascular cognitive impairment (VCI); however, the underlying etiology of this pathological axis remains unclear. METHODSWe investigated pathological mediators across varying severities of VCI in a rat model of chronic cerebral hypoperfusion (CCH). Proteomic analysis guided the evaluation of neuropeptide and non-neuropeptide markers associated with vascular and nonvascular dysfunction, which were correlated with cognitive function to determine their role in VCI. RESULTSProteomic analysis revealed vasomotor dysfunction as the primary pathological pathway in VCI. Microvascular vasoconstriction was the earliest and most persistent event, initiating a cascade of both microvascular and nonvascular dysfunction. Dysregulation of vasoactive neuropeptides was identified as the key driver of this process. CGRP supplementation effectively prevented vasoconstriction, and improving cognitive function in CCH. DISCUSSIONThis study suggests dysregulation of vasoactive neuropeptides plays a central role in CCH pathomechanism, with microvascular vasoconstriction acting as the primary mediator. HIGHLIGHTSO_LINeuropeptides are the primary drivers of dominant pathomechanisms underlying CCH. C_LIO_LIEarly vasoactive neuropeptides dysregulation is a key driver of cognitive decline. C_LIO_LIMicrovascular dysfunction precedes classical non-vascular pathologies in CCH. C_LIO_LICapillary constriction precedes and drives amyloid accumulation in CCH. C_LIO_LICGRP mitigates microvascular constriction, enhancing cognitive function in VCI. C_LI Research in ContextO_LISystematic review: The authors reviewed literature from PubMed and Google Scholar, as well as meeting abstracts and presentations. Neuropeptide dysregulation and microvascular injury are increasingly recognized for involvement in the pathogenesis of VCID; however, the underlying etiology of this pathological axis remains unclear. C_LIO_LIInterpretation: Our evidence shows that early, progressive vasoactive neuropeptide dysregulation drives microvascular constriction, constituting a pivotal mechanism in microvascular dysfunction and subsequent cognitive deterioration in chronic cerebral hypoperfusion. The data further elucidate the significant therapeutic efficacy of pharmacological and non-pharmacological interventions directed at vasoactive neuropeptide pathways, which resulted in marked enhancement of cognitive function. C_LIO_LIFuture directions: Our results indicate that aberrant vasoactive neuropeptide regulation constitutes a fundamental pathophysiological mechanism underlying the development and clinical manifestation of VCID. These findings have potentially substantial implications for the development of novel therapeutic strategies targeting this disorder, which represents the second most common etiology of cognitive deterioration. C_LI