Abstract
SummaryBrain pericytes play a critical role in blood vessel stability and blood–brain barrier maturation. Despite this, how brain pericytes function in these different capacities is only beginning to be understood. Here we show that the forkhead transcription factor Foxc1 is expressed by brain pericytes during development and is critical for pericyte regulation of vascular development in the fetal brain. Conditional deletion of Foxc1 from pericytes and vascular smooth muscle cells leads to late-gestation cerebral micro-hemorrhages as well as pericyte and endothelial cell hyperplasia due to increased proliferation of both cell types. Conditional Foxc1 mutants do not have widespread defects in BBB maturation, though focal breakdown of BBB integrity is observed in large, dysplastic vessels. qPCR profiling of brain microvessels isolated from conditional mutants showed alterations in pericyte-expressed proteoglycans while other genes previously implicated in pericyte–endothelial cell interactions were unchanged. Collectively these data point towards an important role for Foxc1 in certain brain pericyte functions (e.g. vessel morphogenesis) but not others (e.g. barriergenesis).
Highlights
During neural development appropriate growth and maturation of the brain vasculature is essential to meet increasing metabolic needs and to establish a barrier between the brain and potentially damaging agents circulating in the blood
We show that the forkhead transcription factor Foxc1 is expressed by brain pericytes during development and is critical for pericyte regulation of vascular development in the fetal brain
Conditional deletion of Foxc1 from pericytes and vascular smooth muscle cells leads to late-gestation cerebral micro-hemorrhages as well as pericyte and endothelial cell hyperplasia due to increased proliferation of both cell types
Summary
During neural development appropriate growth and maturation of the brain vasculature is essential to meet increasing metabolic needs and to establish a barrier between the brain and potentially damaging agents circulating in the blood. Loss of pericyte coverage does not overtly impact vessel patterning, there are significantly more endothelial cells (ECs) per vessel (hyperplasia), and vessels are susceptible to hemorrhage (Hellstrom et al, 2001; Lindahl et al, 1997). Pericyte-deficient mutants (PDGFB-null or hypomorph and PDGFrb-null) display systemic brain vascular leak and, postnatally, fail to establish proper polarity of the astrocyte endfeet (Armulik et al, 2010; Daneman et al, 2010b). The defects in the fetal brain vasculature of pericyte-deficient mutants provide compelling evidence that pericytes are critical for stabilization and maturation of the neural vascular plexus
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