Ampelopsis grossedentata alleviates vascular cognitive impairment in BCAS mice by regulating VEGFA/KDR/FGFR1-mediated angiogenesis and GSK3β/Bcl-2/Bax-mediated mitochondrial apoptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Ampelopsis grossedentata (Hand.-Mazz.) W.T. Wang (vine tea) is a time-honored ethnomedicine used by the Tujia and Miao minorities in Southern China. It has traditionally been used for "clearing heat and detoxifying", "activating blood and unblocking collaterals", and "subduing liver-yang to resolve phlegm and eliminate turbidity". Its aqueous infusion is consumed as a folk remedy to alleviate vertigo, dizziness, and hypertension-related cardio-cerebrovascular symptoms. These traditional applications suggest its potential therapeutic relevance to chronic cerebral hypoperfusion-induced vascular cognitive impairment.

AIM OF THE STUDY: This study aimed to investigate the protective effects and underlying mechanisms of vine tea aqueous extract against chronic cerebral hypoperfusion-induced vascular cognitive impairment, focusing on its regulation of angiogenic signaling and mitochondrial apoptosis-related pathways.

MATERIALS AND METHODS: The chemical profile of vine tea aqueous extract was characterized by UPLC-Q-TOF-MS, and selected constituents were quantified. Network pharmacology and bioinformatics analysis using the GSE122063 dataset were performed to identify active constituents and candidate therapeutic targets. Molecular docking and 200-ns molecular dynamics simulations evaluated their binding stability. Male C57BL/6 mice were randomly divided into five groups (n = 20/group): Sham, Model, positive control (nimodipine, 11.7 mg/kg), VTL (100 mg/kg), and VTH (200 mg/kg). Vascular cognitive impairment was induced by microcoil-induced bilateral common carotid artery stenosis (BCAS). After a 1-week recovery period, mice received daily oral gavage for 30 days. Behavioral performance was assessed using the open field test, novel object recognition test, and Morris water maze. Cerebral perfusion, CD31-positive microvascular density, myelin integrity, neuronal morphology, neuronal apoptosis, and mitochondrial ultrastructure were assessed. Biochemical assays determined oxidative stress, ATP and lactic acid levels, while related genes and proteins were examined by RT-PCR and Western blotting.

RESULTS: UPLC-Q-TOF-MS identified 31 compounds, among which dihydromyricetin, quercetin, taxifolin, aromadendrin, catechin, epigallocatechin and naringenin (predicted OB ≥ 20%, DL ≥ 0.18) were quantitatively determined. Network analysis identified seven hub targets, including a pro-angiogenic module (VEGFA, KDR, FGFR1) and an apoptosis-related module (GSK3β, RAF1, BCL2, BAX). Molecular docking and dynamics simulations supported stable interactions between the major constituents and hub targets. In BCAS mice, vine tea significantly improved cognitive behavior, restored regional cerebral blood flow (P < 0.01) and increased CD31-positive microvascular density (P < 0.05), while preserving myelin integrity (P < 0.01) and hippocampal neuron survival (P < 0.05). These benefits were accompanied by attenuated mitochondrial ultrastructural damage, increased ATP, SOD, and GSH levels, and reduced lactate and MDA content (P < 0.05), as well as decreased cleaved caspase-3/NeuN double-positive apoptotic neurons (P < 0.05). Mechanistically, VT restored VEGFA/KDR/FGFR1 expression, increased Bcl-2/Bax ratio and GSK3β phosphorylation, and normalized RAF1 hyperphosphorylation, suggesting coordinated regulation of angiogenic signaling and mitochondrial apoptosis-related pathways.

CONCLUSIONS: Vine tea ameliorated cognitive deficits and hippocampal neuronal injury in BCAS mice by restoring VEGFA/KDR/FGFR1-mediated angiogenic signaling and rebalancing GSK3β/RAF1 and Bcl-2/Bax-related mitochondrial apoptotic pathways. These findings suggest vine tea as a promising multi-target ethnomedicinal candidate for vascular cognitive impairment, although the causal link between these two processes warrants further mechanistic validation.