Soluble Endoglin Stimulates Inflammatory and Angiogenic Responses in Microglia That Are Associated with Endothelial Dysfunction
Increased soluble endoglin (sENG) has been observed in human brain arteriovenous malformations (bAVMs). In addition, the overexpression of sENG in concurrence with vascular endothelial growth factor (VEGF)-A has been shown to induce dysplastic vessel formation in mouse brains. However, the underlyin...
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MDPI AG
2022-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/3/1225 |
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| author | Eun S. Park Sehee Kim Derek C. Yao Jude P. J. Savarraj Huimahn Alex Choi Peng Roc Chen Eunhee Kim |
| author_facet | Eun S. Park Sehee Kim Derek C. Yao Jude P. J. Savarraj Huimahn Alex Choi Peng Roc Chen Eunhee Kim |
| author_sort | Eun S. Park |
| collection | DOAJ |
| description | Increased soluble endoglin (sENG) has been observed in human brain arteriovenous malformations (bAVMs). In addition, the overexpression of sENG in concurrence with vascular endothelial growth factor (VEGF)-A has been shown to induce dysplastic vessel formation in mouse brains. However, the underlying mechanism of sENG-induced vascular malformations is not clear. The evidence suggests the role of sENG as a pro-inflammatory modulator, and increased microglial accumulation and inflammation have been 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 the presence of sENG along with VEGF-A overexpression induced dysplastic vessel formation. Remarkably, we observed increased microglial activation around dysplastic vessels with the expression of NLRP3, an 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 levels of angiogenic factors (Notch-1 and TGFβ) and pERK1/2 in ECs but it decreased the level of 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 express angiogenic/inflammatory molecules which may be involved in EC dysfunction. Our study corroborates the contribution of microglia to the pathology of sENG-associated vascular malformations. |
| first_indexed | 2024-03-09T23:50:10Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:50:10Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-ebfbc3a8af7c4062b98a9ca1b43d0fc32023-11-23T16:36:59ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-01-01233122510.3390/ijms23031225Soluble Endoglin Stimulates Inflammatory and Angiogenic Responses in Microglia That Are Associated with Endothelial DysfunctionEun S. Park0Sehee Kim1Derek C. Yao2Jude P. J. Savarraj3Huimahn Alex Choi4Peng Roc Chen5Eunhee Kim6Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USAVivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USAVivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USAVivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USAVivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USAVivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USAVivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USAIncreased soluble endoglin (sENG) has been observed in human brain arteriovenous malformations (bAVMs). In addition, the overexpression of sENG in concurrence with vascular endothelial growth factor (VEGF)-A has been shown to induce dysplastic vessel formation in mouse brains. However, the underlying mechanism of sENG-induced vascular malformations is not clear. The evidence suggests the role of sENG as a pro-inflammatory modulator, and increased microglial accumulation and inflammation have been 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 the presence of sENG along with VEGF-A overexpression induced dysplastic vessel formation. Remarkably, we observed increased microglial activation around dysplastic vessels with the expression of NLRP3, an 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 levels of angiogenic factors (Notch-1 and TGFβ) and pERK1/2 in ECs but it decreased the level of 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 express angiogenic/inflammatory molecules which may be involved in EC dysfunction. Our study corroborates the contribution of microglia to the pathology of sENG-associated vascular malformations.https://www.mdpi.com/1422-0067/23/3/1225brain arteriovenous malformation (bAVM)soluble endoglin (sENG)microgliaendothelial cells (ECs)inflammationangiogenesis |
| spellingShingle | Eun S. Park Sehee Kim Derek C. Yao Jude P. J. Savarraj Huimahn Alex Choi Peng Roc Chen Eunhee Kim Soluble Endoglin Stimulates Inflammatory and Angiogenic Responses in Microglia That Are Associated with Endothelial Dysfunction International Journal of Molecular Sciences brain arteriovenous malformation (bAVM) soluble endoglin (sENG) microglia endothelial cells (ECs) inflammation angiogenesis |
| title | Soluble Endoglin Stimulates Inflammatory and Angiogenic Responses in Microglia That Are Associated with Endothelial Dysfunction |
| title_full | Soluble Endoglin Stimulates Inflammatory and Angiogenic Responses in Microglia That Are Associated with Endothelial Dysfunction |
| title_fullStr | Soluble Endoglin Stimulates Inflammatory and Angiogenic Responses in Microglia That Are Associated with Endothelial Dysfunction |
| title_full_unstemmed | Soluble Endoglin Stimulates Inflammatory and Angiogenic Responses in Microglia That Are Associated with Endothelial Dysfunction |
| title_short | Soluble Endoglin Stimulates Inflammatory and Angiogenic Responses in Microglia That Are Associated with Endothelial Dysfunction |
| title_sort | soluble endoglin stimulates inflammatory and angiogenic responses in microglia that are associated with endothelial dysfunction |
| topic | brain arteriovenous malformation (bAVM) soluble endoglin (sENG) microglia endothelial cells (ECs) inflammation angiogenesis |
| url | https://www.mdpi.com/1422-0067/23/3/1225 |
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