Collagen IV Deficiency Causes Hypertrophic Remodeling and Endothelium-dependent Hyperpolarization in Small Vessel Disease with Intracerebral Hemorrhage

Overview

Journal EBioMedicine

Specialty Biomedical Engineering

Date 2024 Aug 31

PMID 39216230

Authors

Sarah McNeilly

Cameron R Thomson

Laura Gonzalez-Trueba

Yuan Yan Sin

Alessandra Granata

Graham Hamilton

Michelle Lee

Erin Boland

John D McClure

Cristina Lumbreras-Perales

Alisha Aman

Apoorva A Kumar

Marco Cantini

Caglar Gok

Delyth Graham

Yasuko Tomono

Christopher D Anderson

Yinhui Lu

Colin Smith

Hugh S Markus

Marc Abramowicz

Catheline Vilain

Rustam Al-Shahi Salman

Manuel Salmeron-Sanchez

Atticus H Hainsworth

William Fuller

Karl E Kadler

Neil J Bulleid

Tom Van Agtmael

Affiliations

Soon will be listed here.

Abstract

Background: Genetic variants in COL4A1 and COL4A2 (encoding collagen IV alpha chain 1/2) occur in genetic and sporadic forms of cerebral small vessel disease (CSVD), a leading cause of stroke, dementia and intracerebral haemorrhage (ICH). However, the molecular mechanisms of CSVD with ICH and COL4A1/COL4A2 variants remain obscure.

Methods: Vascular function and molecular investigations in mice with a Col4a1 missense mutation and heterozygous Col4a2 knock-out mice were combined with analysis of human brain endothelial cells harboring COL4A1/COL4A2 mutations, and brain tissue of patients with sporadic CSVD with ICH.

Findings: Col4a1 missense mutations cause early-onset CSVD independent of hypertension, with enhanced vasodilation of small arteries due to endothelial dysfunction, vascular wall thickening and reduced stiffness. Mechanistically, the early-onset dysregulated endothelium-dependent hyperpolarization (EDH) is due to reduced collagen IV levels with elevated activity and levels of endothelial Ca-sensitive K channels. This results in vasodilation via the Na/K pump in vascular smooth muscle cells. Our data support this endothelial dysfunction preceding development of CSVD-associated ICH is due to increased cytoplasmic Ca levels in endothelial cells. Moreover, cerebral blood vessels of patients with sporadic CSVD show genotype-dependent mechanisms with wall thickening and lower collagen IV levels in those harboring common non-coding COL4A1/COL4A2 risk alleles.

Interpretation: COL4A1/COL4A2 variants act in genetic and sporadic CSVD with ICH via dysregulated EDH, and altered vascular wall thickness and biomechanics due to lower collagen IV levels and/or mutant collagen IV secretion. These data highlight EDH and collagen IV levels as potential treatment targets.

Funding: MRC, Wellcome Trust, BHF.

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