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

## TL;DR

This study shows that vasoactive neuropeptide dysregulation causes microvascular issues that lead to cognitive decline in vascular cognitive impairment.

## Contribution

The study identifies vasoactive neuropeptide dysregulation as a novel mechanism driving microvascular dysfunction in vascular cognitive impairment.

## Key findings

- Microvascular vasoconstriction is the earliest and most persistent event in vascular cognitive impairment.
- Dysregulation of vasoactive neuropeptides is the key driver of vascular and non-vascular dysfunction in chronic cerebral hypoperfusion.
- Calcitonin gene-related peptide (CGRP) supplementation prevents vasoconstriction and improves cognitive function in chronic cerebral hypoperfusion.

## Abstract

Neuropeptide dysregulation and microvascular injury are involved in pathogenesis of vascular cognitive impairment (VCI); however, the underlying etiology of this pathological axis remains unclear.

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.

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.

This study suggests dysregulation of vasoactive neuropeptides plays a central role in CCH pathomechanism, with microvascular vasoconstriction acting as the primary mediator.

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.

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.