Vasculogenesis and Angiogenesis
Vasculogenesis of the cerebral vasculature occurs outside the brain with the formation of a perineural plexus, from which capillary sprouts penetrate the neural tube. The subsequent elaboration of the cerebral vasculature occurs by angiogenesis. Cerebral angiogenesis is tightly linked to the proliferation and growth of neurons and glia, and appears to be mediated at least in part by hypoxia-inducible transcription factors (HIFs).
HIFs up-regulate the production of vascular endothelial growth factor (VEGF), which in turn stimulates endothelial cell proliferation, migration, and survival. Angiogenesis is down-regulated once the vascular bed is established (shortly after birth), but proceeds at a slower pace throughout life. In animal models, for example, angiogenesis has been observed in the healthy adult brain in response to a variety of stimuli that increase neural activity, including exercise, exposure to enriched sensory environments, and certain hormones. Brain angiogenesis can also undergo dramatic local up-regulation in response to disease states such as brain tumor, stroke, or trauma.
VMBs are characterized by activated angiogenesis.
Angiogenesis is actively regulated by surrounding tissue cells, and also by resident and circulating immune cells
. Angiogenic processes in the CNS are likely to differ from those in other organs, not only because of the specialized parenchymal cell types involved, but also because brain vascular endothelial cells themselves have unique properties. Most prominent of these are (1) the presence of tight junctions and (2) the formation of specialized contacts with astrocyte endfeet. These morphological features contribute to the special permeability properties of blood-brain barrier (BBB), and appear to be disrupted in CCMs.
Formation and maintenance of the BBB requires cross-talk between the cells of the neurovascular unit (i.e., vascular endothelial cells, neurons, astrocytes, and pericytes), much of which appears to be mediated by cell adhesion molecules
and molecules of the extracellular matrix. Reciprocal communication between the cells of the neurovascular unit regulates not only BBB formation, but also angiogenesis and neurogenesis. In stroke, for example, there is recruitment of new endothelial cells to ischemic tissue, and new vessels in turn attract neural precursors. Hence, it is possible that defects in signaling between the cells of the neurovascular unit contribute to the development of VMBs, and also to their adverse impact on surrounding neural tissue.
A fourth population of cells likely to be important in VMB pathogenesis is immune cells. VMB lesions frequently show marked infiltrations of inflammatory cells and local up-regulation of inflammatory cytokines, some of which are powerful regulators of angiogenesis and vascular permeability
. In addition, polymorphisms in cytokine genes have been associated with increased risk of hemorrhage for sporadic brain AVMs.
"However, the truth in science ultimately emerges, although sometimes it takes a very long time," Arthur Silverstein, Autoimmunity: A History of the Early Struggle for Recognition