Park, E.S.; Kim, S.; Yao, D.C.; Savarraj, J.P.J.; Choi, H.A.; Chen, P.R.; Kim, E. Soluble Endoglin Stimulates Inflammatory and Angiogenic Responses in Microglia That Are Associated with Endothelial Dysfunction. Int. J. Mol. Sci.2022, 23, 1225.
Park, E.S.; Kim, S.; Yao, D.C.; Savarraj, J.P.J.; Choi, H.A.; Chen, P.R.; Kim, E. Soluble Endoglin Stimulates Inflammatory and Angiogenic Responses in Microglia That Are Associated with Endothelial Dysfunction. Int. J. Mol. Sci. 2022, 23, 1225.
Park, E.S.; Kim, S.; Yao, D.C.; Savarraj, J.P.J.; Choi, H.A.; Chen, P.R.; Kim, E. Soluble Endoglin Stimulates Inflammatory and Angiogenic Responses in Microglia That Are Associated with Endothelial Dysfunction. Int. J. Mol. Sci.2022, 23, 1225.
Park, E.S.; Kim, S.; Yao, D.C.; Savarraj, J.P.J.; Choi, H.A.; Chen, P.R.; Kim, E. Soluble Endoglin Stimulates Inflammatory and Angiogenic Responses in Microglia That Are Associated with Endothelial Dysfunction. Int. J. Mol. Sci. 2022, 23, 1225.
Abstract
Increased soluble endoglin (sENG) were observed in human brain arteriovenous malformations (bAVMs), and overexpression of sENG with vascular endothelial growth factor (VEGF)-A induced dysplastic vessel formation in mouse brain. However, the underlying mechanism of sENG-induced vascular malformations is not clear. While evidence suggests the role of sENG as a pro-inflammatory modulator, increased microglial accumulation and inflammations were observed in bAVMs. Therefore, we hypothesized that microglia mediate sENG-induced inflammation and endothelial cell (EC) dysfunction in bAVMs. In this study, we confirmed that sENG with VEGF-A overexpression induced dysplastic vessel formation. Remarkably, there were increased microglial activation around dysplastic vessels with expression of NLRP3, inflammasome marker. We found that sENG increased the gene expression of VEGF-A, pro-inflammatory cytokines/inflammasome mediators (TNF-α, IL-6, NLRP3, ASC, Caspase-1, and IL-1β), and proteolytic enzyme (MMP-9) in BV2 microglia. The conditioned media from sENG-treated BV2 (BV2-sENG-CM) significantly increased angiogenic factors (Notch-1 and TGFβ) and pERK1/2 in ECs while it decreased IL-17RD, an anti-angiogenic mediator. Finally, the BV2-sENG-CM significantly increased EC migration and tube formation. Together, our study demonstrates that sENG provokes microglia to release angiogenic/inflammatory responses which may be involved in EC dysfunction. Our study suggests the contribution of microglia in the pathology of sENG-associated vascular malformations.
Biology and Life Sciences, Immunology and Microbiology
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