Abstract
Upon severe head injury (HI), blood vessels of the meninges and brain parenchyma are inevitably damaged. While limited vascular regeneration of the injured brain has been studied extensively, our understanding of meningeal vascular regeneration following head injury is quite limited. Here, we identify key pathways governing meningeal vascular regeneration following HI. Rapid and complete vascular regeneration in the meninges is predominantly driven by VEGFR2 signaling. Substantial increase of VEGFR2 is observed in both human patients and mouse models of HI, and endothelial cell-specific deletion of Vegfr2 in the latter inhibits meningeal vascular regeneration. We further identify the facilitating, stabilizing and arresting roles of Tie2, PDGFRβ and Dll4 signaling, respectively, in meningeal vascular regeneration. Prolonged inhibition of this angiogenic process following HI compromises immunological and stromal integrity of the injured meninges. These findings establish a molecular framework for meningeal vascular regeneration after HI, and may guide development of wound healing therapeutics.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Blood Vessels / metabolism
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Blood Vessels / pathology
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism
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Cerebrovascular Circulation
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Craniocerebral Trauma / genetics*
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Craniocerebral Trauma / metabolism
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Craniocerebral Trauma / pathology
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Disease Models, Animal
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Endothelial Cells / metabolism*
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Endothelial Cells / pathology
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Gene Expression Regulation / genetics
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Humans
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Macrophages / metabolism
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Macrophages / pathology
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Meninges / injuries
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Meninges / metabolism
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Mice
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Mice, Knockout
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Neovascularization, Physiologic / genetics*
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Receptor, Platelet-Derived Growth Factor beta / genetics
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Receptor, Platelet-Derived Growth Factor beta / metabolism
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Receptor, TIE-2 / genetics
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Receptor, TIE-2 / metabolism
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Regeneration / genetics*
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Signal Transduction / genetics*
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Vascular Endothelial Growth Factor Receptor-2 / genetics*
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
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Wound Healing / genetics
Substances
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Adaptor Proteins, Signal Transducing
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Calcium-Binding Proteins
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DLL4 protein, mouse
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Kdr protein, mouse
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Receptor, Platelet-Derived Growth Factor beta
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Receptor, TIE-2
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Tek protein, mouse
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Vascular Endothelial Growth Factor Receptor-2