Increased Collagen I/Collagen III Ratio Is Associated with Hemorrhage in Brain Arteriovenous Malformations in Human and Mouse
Author:
Shabani Zahra12, Schuerger Joana12, Zhu Xiaonan12, Tang Chaoliang12ORCID, Ma Li12ORCID, Yadav Alka12, Liang Rich12, Press Kelly12, Weinsheimer Shantel12, Schmidt Annika12, Wang Calvin12, Sekhar Abinav12, Nelson Jeffrey12, Kim Helen12, Su Hua12ORCID
Affiliation:
1. Center for Cerebrovascular Research, University of California, San Francisco, CA 94143, USA 2. Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143, USA
Abstract
Background: The increase in the collagen I (COL I)/COL III ratio enhances vessel wall stiffness and renders vessels less resistant to blood flow and pressure changes. Activated microglia enhance inflammation-induced fibrosis. Hypotheses: The COL I/COL III ratio in human and mouse brain arteriovenous malformations (bAVMs) is associated with bAVM hemorrhage, and the depletion of microglia decreases the COL I/COL III ratio and hemorrhage. Method: COL I, COL III, and hemorrhages were analyzed in 12 human bAVMs and 6 control brains, and mouse bAVMs induced in three mouse lines with activin receptor-like kinase 1 (n = 7) or endoglin (n = 7) deleted in the endothelial cells or brain focally (n = 5). The controls for the mouse study were no-gene-deleted litter mates. Mouse bAVMs were used to test the relationships between the Col I/Col III ratio and hemorrhage and whether the transient depletion of microglia reduces the Col I/Col III ratio and hemorrhage. Results: The COL I/COL III ratio was higher in the human and mouse bAVMs than in controls. The microhemorrhage in mouse bAVMs was positively correlated with the Col I/Col III ratio. Transient depletion of microglia reduced the Col I/Col III ratio and microhemorrhage. Conclusions: The COL I/COL III ratio in the bAVMs was associated with bAVM hemorrhage. The depletion of microglia reduced the bAVM Col I/Col III ratio and hemorrhage.
Funder
National Institutes of Health Michael Ryan Zodda Foundation
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