KRIT1 loss-mediated upregulation of NOX1 in stromal cells promotes paracrine pro-angiogenic responses.

Publisher: Elsevier Science Ltd Country of Publication: England NLM ID: 8904683 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-3913 (Electronic) Linking ISSN: 08986568 NLM ISO Abbreviation: Cell Signal Subsets: MEDLINE

Publication: Oxford : Elsevier Science Ltd
Original Publication: Oxford ; New York : Pergamon Press, 1988-

Neovascularization, Physiologic*/drug effects ; Paracrine Communication*/drug effects ; Up-Regulation*/drug effects; KRIT1 Protein/*metabolism ; NADPH Oxidase 1/*metabolism; Animals ; Antigens, CD/metabolism ; Cadherins/metabolism ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Culture Media, Conditioned/pharmacology ; Cyclooxygenase 2/metabolism ; Dinoprostone/biosynthesis ; Fibroblasts/drug effects ; Fibroblasts/metabolism ; Human Umbilical Vein Endothelial Cells/drug effects ; Human Umbilical Vein Endothelial Cells/metabolism ; Humans ; Matrix Metalloproteinase 2/metabolism ; Mice, Knockout ; Stromal Cells/drug effects ; Stromal Cells/metabolism ; Vascular Endothelial Growth Factor A/metabolism

Cerebral cavernous malformation (CCM) is a cerebrovascular disorder of proven genetic origin characterized by abnormally dilated and leaky capillaries occurring mainly in the central nervous system, with a prevalence of 0.3-0.5% in the general population. Genetic studies have identified causative mutations in three genes, CCM1/KRIT1, CCM2 and CCM3, which are involved in the maintenance of vascular homeostasis. However, distinct studies in animal models have clearly shown that CCM gene mutations alone are not sufficient to cause CCM disease, but require additional contributing factors, including stochastic events of increased oxidative stress and inflammation. Consistently, previous studies have shown that up-regulation of NADPH oxidase-mediated production of reactive oxygen species (ROS) in KRIT1 deficient endothelium contributes to the loss of microvessel barrier function. In this study, we demonstrate that KRIT1 loss-of-function in stromal cells, such as fibroblasts, causes the up-regulation of NADPH oxidase isoform 1 (NOX1) and the activation of inflammatory pathways, which in turn promote an enhanced production of proangiogenic factors, including vascular endothelial growth factor (VEGF) and prostaglandin E2 (PGE2). Furthermore and importantly, we show that conditioned media from KRIT1 null fibroblasts induce proliferation, migration, matrix metalloproteinase 2 (MMP2) activation and VE-cadherin redistribution in wild type human endothelial cells. Taken together, our results demonstrate that KRIT1 loss-of-function in stromal cells affects the surrounding microenvironment through a NOX1-mediated induction and release of angiogenic factors that are able to promote paracrine proangiogenic responses in human endothelial cells, thus pointing to a novel role for endothelial cell-nonautonomous effects of KRIT1 mutations in CCM pathogenesis, and opening new perspectives for disease prevention and treatment.
(Copyright © 2020 Elsevier Inc. All rights reserved.)

Keywords: CCM; COX-2; Cerebrovascular disease; KRIT1; NOX1; PGE2

0 (Antigens, CD)
0 (Cadherins)
0 (Culture Media, Conditioned)
0 (KRIT1 Protein)
0 (Krit1 protein, mouse)
0 (Vascular Endothelial Growth Factor A)
0 (cadherin 5)
EC 1.14.99.1 (Cyclooxygenase 2)
EC 1.6.3.- (NADPH Oxidase 1)
EC 1.6.3.- (NOX1 protein, mouse)
EC 3.4.24.24 (Matrix Metalloproteinase 2)
K7Q1JQR04M (Dinoprostone)

Date Created: 20200110 Date Completed: 20210609 Latest Revision: 20210609

20250114

10.1016/j.cellsig.2020.109527

31917192