Absence of endothelial α5β1 integrin triggers early onset of experimental autoimmune encephalomyelitis due to reduced vascular remodeling and compromised vascular integrity
Abstract Early in the development of multiple sclerosis (MS) and its mouse model experimental autoimmune encephalomyelitis (EAE), vascular integrity is compromised. This is accompanied by a marked vascular remodeling response, though it is currently unclear whether this is an adaptive vascular repai...
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| Format: | Article |
| Language: | English |
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BMC
2019-01-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40478-019-0659-9 |
| _version_ | 1819043869433528320 |
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| author | Ravi Kant Sebok K. Halder Gregory J. Bix Richard Milner |
| author_facet | Ravi Kant Sebok K. Halder Gregory J. Bix Richard Milner |
| author_sort | Ravi Kant |
| collection | DOAJ |
| description | Abstract Early in the development of multiple sclerosis (MS) and its mouse model experimental autoimmune encephalomyelitis (EAE), vascular integrity is compromised. This is accompanied by a marked vascular remodeling response, though it is currently unclear whether this is an adaptive vascular repair mechanism or is part of the pathogenic process. In light of the well-described angiogenic role for the α5β1 integrin, the goal of this study was to evaluate how genetic deletion of endothelial α5 integrin (α5-EC-KO mice) impacts vascular remodeling and repair following vascular disruption during EAE pathogenesis, and how this subsequently influences clinical progression and inflammatory demyelination. Immunofluorescence staining revealed that fibronectin and α5 integrin expression were strongly upregulated on spinal cord blood vessels during the pre-symptomatic phase of EAE. Interestingly, α5-EC-KO mice showed much earlier onset and faster progression of EAE, though peak disease severity and chronic disease activity were no different from wild-type mice. At the histological level, earlier disease onset in α5-EC-KO mice correlated with accelerated vascular disruption and increased leukocyte infiltration into the spinal cord. Significantly, spinal cord blood vessels in α5-EC-KO mice showed attenuated endothelial proliferation during the pre-symptomatic phase of EAE which resulted in reduced vascular density at later time-points. Under pro-inflammatory conditions, primary cultures of α5KO brain endothelial cells showed reduced proliferation potential. These findings suggest that α5β1 integrin-mediated angiogenic remodeling represents an important repair mechanism that counteracts vascular disruption during the early stages of EAE development. |
| first_indexed | 2024-12-21T10:03:38Z |
| format | Article |
| id | doaj.art-94b9874d96744978a9d055bd5e825c49 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-21T10:03:38Z |
| publishDate | 2019-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-94b9874d96744978a9d055bd5e825c492022-12-21T19:07:53ZengBMCActa Neuropathologica Communications2051-59602019-01-017111110.1186/s40478-019-0659-9Absence of endothelial α5β1 integrin triggers early onset of experimental autoimmune encephalomyelitis due to reduced vascular remodeling and compromised vascular integrityRavi Kant0Sebok K. Halder1Gregory J. Bix2Richard Milner3Department of Molecular Medicine, MEM-151, The Scripps Research InstituteDepartment of Molecular Medicine, MEM-151, The Scripps Research InstituteSanders-Brown Center on Aging and Department of Neurology, Neurosurgery and Neuroscience, University of KentuckyDepartment of Molecular Medicine, MEM-151, The Scripps Research InstituteAbstract Early in the development of multiple sclerosis (MS) and its mouse model experimental autoimmune encephalomyelitis (EAE), vascular integrity is compromised. This is accompanied by a marked vascular remodeling response, though it is currently unclear whether this is an adaptive vascular repair mechanism or is part of the pathogenic process. In light of the well-described angiogenic role for the α5β1 integrin, the goal of this study was to evaluate how genetic deletion of endothelial α5 integrin (α5-EC-KO mice) impacts vascular remodeling and repair following vascular disruption during EAE pathogenesis, and how this subsequently influences clinical progression and inflammatory demyelination. Immunofluorescence staining revealed that fibronectin and α5 integrin expression were strongly upregulated on spinal cord blood vessels during the pre-symptomatic phase of EAE. Interestingly, α5-EC-KO mice showed much earlier onset and faster progression of EAE, though peak disease severity and chronic disease activity were no different from wild-type mice. At the histological level, earlier disease onset in α5-EC-KO mice correlated with accelerated vascular disruption and increased leukocyte infiltration into the spinal cord. Significantly, spinal cord blood vessels in α5-EC-KO mice showed attenuated endothelial proliferation during the pre-symptomatic phase of EAE which resulted in reduced vascular density at later time-points. Under pro-inflammatory conditions, primary cultures of α5KO brain endothelial cells showed reduced proliferation potential. These findings suggest that α5β1 integrin-mediated angiogenic remodeling represents an important repair mechanism that counteracts vascular disruption during the early stages of EAE development.http://link.springer.com/article/10.1186/s40478-019-0659-9EndothelialExtracellular matrixFibronectinIntegrinExperimental autoimmune encephalomyelitisBlood-brain barrier |
| spellingShingle | Ravi Kant Sebok K. Halder Gregory J. Bix Richard Milner Absence of endothelial α5β1 integrin triggers early onset of experimental autoimmune encephalomyelitis due to reduced vascular remodeling and compromised vascular integrity Acta Neuropathologica Communications Endothelial Extracellular matrix Fibronectin Integrin Experimental autoimmune encephalomyelitis Blood-brain barrier |
| title | Absence of endothelial α5β1 integrin triggers early onset of experimental autoimmune encephalomyelitis due to reduced vascular remodeling and compromised vascular integrity |
| title_full | Absence of endothelial α5β1 integrin triggers early onset of experimental autoimmune encephalomyelitis due to reduced vascular remodeling and compromised vascular integrity |
| title_fullStr | Absence of endothelial α5β1 integrin triggers early onset of experimental autoimmune encephalomyelitis due to reduced vascular remodeling and compromised vascular integrity |
| title_full_unstemmed | Absence of endothelial α5β1 integrin triggers early onset of experimental autoimmune encephalomyelitis due to reduced vascular remodeling and compromised vascular integrity |
| title_short | Absence of endothelial α5β1 integrin triggers early onset of experimental autoimmune encephalomyelitis due to reduced vascular remodeling and compromised vascular integrity |
| title_sort | absence of endothelial α5β1 integrin triggers early onset of experimental autoimmune encephalomyelitis due to reduced vascular remodeling and compromised vascular integrity |
| topic | Endothelial Extracellular matrix Fibronectin Integrin Experimental autoimmune encephalomyelitis Blood-brain barrier |
| url | http://link.springer.com/article/10.1186/s40478-019-0659-9 |
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