Is Fibronectin a Major Driver of Cerebral Angiogenesis?

The extracellular matrix (ECM) is an important regulator of angiogenesis and vascular remodeling. We have shown that angiogenic vessels in the developing central nervous system (CNS) express high levels of fibronectin and the fibronectin receptor α5β1 integrin. In keeping with an angiogenic role for fibronectin in other systems, this implies that fibronectin may provide an important angiogenic drive in the CNS. To investigate whether this mechanism also applies to the adult CNS, we examined these events in a mouse model of cerebral hypoxia, in which mice are exposed to 8% O2. Over a 2-week period, this results in a robust increase (50%) in vessel density in the brains of these mice. Immunohistochemistry and western blot revealed that hypoxia strongly induced fibronectin and brain endothelial cell (BEC) expression of the fibronectin receptors, α5β1 and αvβ3 integrins. To directly test whether these BEC integrins are required for cerebral angiogenesis, the hypoxic response was examined in transgenic mice deficient in either the α5 or β3 integrins. β3 integrin KO mice showed no obvious defect in the angiogenic response, and actually showed an increased BEC mitotic index, which correlated with compensatory increased α5 integrin expression. In contrast, mice lacking endothelial expression of α5 integrins (α5-EC-KO mice) showed an attenuated angiogenic response which was paralleled by delayed BEC proliferation. Taken together, these studies suggest that αvβ3 integrin is not essential for cerebral angiogenesis, but demonstrate an important angiogenic role for the α5β1 integrin in promoting BEC proliferation. 

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Hosted by: Dr. Colin Willis