Is Fibronectin a Major Driver of Cerebral Angiogenesis?

Dr. Milner received a BS in Physiology from the University of Leeds, an MD, Medicine and Surgery, and a PhD in Developmental Neurobiology from the University of Cambridge. He has received several awards in his field such as a Wellcome Trust Career Development Fellowship and a Harry Weaver Neuroscience Scholar Award from the National Multiple Sclerosis Society.

Abstract:
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 _5_1 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, _5_1 and _v_3 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 _5 or _3 integrins. _3 integrin KO mice showed no obvious defect in the angiogenic response, and actually showed an increased BEC mitotic index, which correlated with compensatory increased _5 integrin expression. In contrast, mice lacking endothelial expression of _5 integrins (_5-EC-KO mice) showed an attenuated angiogenic response which was paralleled by delayed BEC proliferation. Taken together, these studies suggest that _v_3 integrin is not essential for cerebral angiogenesis, but demonstrate an important angiogenic role for the _5_1 integrin in promoting BEC proliferation.