CNS resident macrophages enhance dysfunctional angiogenesis and circulating monocytes infiltration in brain arteriovenous malformation

Li Ma; Xiaonan Zhu; Chaoliang Tang; Peipei Pan; Alka Yadav; Rich Liang; Kelly Press; Jeffrey Nelson; Hua Su

doi:10.1177/0271678X241236008

CNS resident macrophages enhance dysfunctional angiogenesis and circulating monocytes infiltration in brain arteriovenous malformation

J Cereb Blood Flow Metab. 2024 Feb 28:271678X241236008. doi: 10.1177/0271678X241236008. Online ahead of print.

Authors

Li Ma^{1

2}, Xiaonan Zhu^{1

2}, Chaoliang Tang^{1

2}, Peipei Pan^{1

2}, Alka Yadav^{1

2}, Rich Liang^{1

2}, Kelly Press^{1

2}, Jeffrey Nelson^{1

2}, Hua Su^{1

2}

Affiliations

¹ Center for Cerebrovascular Research, University of California, San Francisco, California, USA.
² Department of Anesthesia and Perioperative Care, University of California, San Francisco, California, USA.

PMID: 38415628
DOI: 10.1177/0271678X241236008

Abstract

Myeloid immune cells are abundant in both ruptured and unruptured brain arteriovenous malformations (bAVMs). The role of central nervous system (CNS) resident and circulating monocyte-derived macrophages in bAVM pathogenesis has not been fully understood. We hypothesize that CNS resident macrophages enhance bAVM development and hemorrhage. RNA sequencing using cultured endothelial cells (ECs) and mouse bAVM samples revealed that downregulation of two bAVM causative genes, activin-like kinase 1 (ALK1) or endoglin, increased inflammation and innate immune signaling. To understand the role of CNS resident macrophages in bAVM development and hemorrhage, we administrated a colony-stimulating factor 1 receptor inhibitor to bAVM mice with brain focal Alk1 deletion. Transient depletion of CNS resident macrophages at an early stage of bAVM development mitigated the phenotype severity of bAVM, including a prolonged inhibition of angiogenesis, dysplastic vasculature formation, and infiltration of CNS resident and circulating monocyte-derived macrophages during bAVM development. Transient depletion of CNS resident macrophages increased EC tight junction protein expression, reduced the number of dysplasia vessels and severe hemorrhage in established bAVMs. Thus, EC AVM causative gene mutation can activate CNS resident macrophages promoting bAVM progression. CNS resident macrophage could be a therapeutic target to mitigate the development and severity of bAVMs.

Keywords: Arteriovenous malformation; CNS resident macrophages; angiogenesis; colony-stimulating factor 1 receptor inhibitor; myeloid derived macrophages.