Vasoactive neuropeptide dysregulation: A novel mechanism of microvascular dysfunction in vascular cognitive impairment

INTRODUCTION: Neuropeptide dysregulation and microvascular injury are involved in pathogenesis of vascular cognitive impairment (VCI); however, the underlying etiology of this pathological axis remains unclear. METHODS: We 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 non-vascular dysfunction, which were correlated with cognitive function to determine their role in VCI. RESULTS: Proteomic 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 non-vascular dysfunction. Dysregulation of vasoactive neuropeptides was identified as the key driver of this process. Calcitonin gene-related peptide (CGRP) supplementation effectively prevented vasoconstriction, and improved cognitive function in CCH. DISCUSSION: This study suggests dysregulation of vasoactive neuropeptides plays a central role in CCH pathomechanism, with microvascular vasoconstriction acting as the primary mediator. HIGHLIGHTS: Neuropeptides are the primary drivers of dominant pathomechanisms underlying chronic cerebral hypoperfusion (CCH). Early vasoactive neuropeptide dysregulation is a key driver of cognitive decline. Microvascular dysfunction precedes classical non-vascular pathologies in CCH. Capillary constriction precedes and drives amyloid accumulation in CCH. CGRP mitigates microvascular constriction, enhancing cognitive function in VCI.