PIGF knockout delays brain vessel growth and maturation upon systemic hypoxic challenge

In this study, we have investigated the potential role of placental growth factor (PIGF) in hypoxia-induced brain angiogenesis. To this end, PIGF wild-type (PIGF(+/+)) and PIGF knockout (PIGF(-/-)) mice were exposed to whole body hypoxia (10% oxygen) for 7, 14, and 21 days. PIGF(+/+) animals exhibited a significant similar to 40% increase in angiogenesis after 7 days of hypoxia compared with controls, while in PIGF(-/-) this effect only occurred after 14 days of hypoxia. No differences in pericyte/smooth muscle cell (SMC) coverage between the two genotypes were observed. After 14 days of hypoxia, PIGF(-/-)microvessels had a significant increase in fibrinogen accumulation and extravasation compared with those of PIGF(+/+), which correlated with endothelial cell disruption of the tight junction protein claudin-5. These vessels displayed large lumens, were surrounded by reactive astrocytes, lacked both pericyte/SMC coverage and endothelial vascular endothelial growth factor expression, and regressed after 21 days of hypoxia. Vascular endothelial growth factor expression levels were found to be significantly lower in the frontal cortex of PIGF(-/-) compared with those in PIGF(+/+) animals during the first 5 days of hypoxia, which in combination with the lack of PIGF may have contributed to the delayed angiogenic response and the prothrombotic phenotype observed in the PIGF(-/-) animals. Journal of Cerebral Blood Flow & Metabolism (2012) 32, 663-675; doi:10.1038/jcbfm.2011.167; published online 30 November 2011