VEGF-A angiogenesis induces a stable neovasculature in adult murine brain.
Angiogenesis is a critical component of stroke, head injury, cerebral vascular malformation development, and brain tumor growth. An understanding of the mechanisms of adult cerebral angiogenesis is fundamental to therapeutic vessel modulation for these diseases. To study angiogenesis in the central nervous system, we injected an adenoviral vector engineered to express vascular endothelial growth factor (VEGF-A164) into adult murine striatum. Vector-infected astrocytes expressed VEGF-A164 resulting in vascular permeability, hemorrhage, and the formation of greatly enlarged "mother" vessels. Subsequently, endothelial cells and pericytes lining mother vessels proliferated and assembled into glomeruloid bodies, complex cellular arrays interspersed by small vessel lumens. As VEGF-A164 expression declined, glomeruloid bodies involuted through apoptotic processes to engender numerous small daughter vessels. Characterized by modestly enlarged lumens with prominent pericyte coverage, daughter vessels were distributed with a density greater than normal cerebral vessels. Daughter vessels remained stable and patent to 16 months and represented the final stage of VEGF-A-induced cerebral angiogenesis. Together, these findings provide a mechanistic understanding of angiogenesis in cerebral disease processes. Furthermore, the long-term stability of daughter vessels in the absence of exogenous VEGF-A164 expression suggests that VEGF-A may enable therapeutic angiogenesis in brain.
Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. sstiver@bidmc.harvard.edu
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Stiver
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Tan
L F
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Brown
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Hedley-Whyte
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Dvorak
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000821:virology; D001921:Brain / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism; D003342:Corpus Striatum / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D007276:Injections, Intraventricular; D051379:Mice; D008819:Mice, Nude; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics*
D042461:Vascular Endothelial Growth Factor A