The importance of astroglial cells in ischemia, regeneration and angiogenesis

Abstract

Astrocytes in the CNS communicate with both neurons and blood vessels. In many CNS pathologies, astrocytes respond by becoming reactive. Whether their performance at this stage is beneficial or detrimental for CNS function is unclear. The impact of reactive gliosis in brain ischemia and regeneration was studied using a mouse model where the astroglial reactivity is altered - these mice lack astroglial intermediate filaments (IFs), a part of the cytoskeleton. We found that reactive astrocytes provide protection in brain ischemia. However, they impose an obstacle for neuroregeneration. This mouse model was further utilized to study the function of astroglial IFs in the retina. For normal structure and function of the retina, IFs of astroglial cells are dispensable. However, upon exposure to extreme mechanical stress, they provide structural support to a specific part of the retina but, interestingly, in the ischemic retina, the absence of IFs diminishes the usual vascular lesions. Vision impairment in ischemia-induced retinopathies like diabetic retinopathy is caused by pathological angiogenesis - blood vessel formation. Astrocytes are highly involved in the pathogenesis, since they overexpress the angiogenic growth factor VEGF-A. The absence of astrocytic IFs does not affect the VEGF-A expression. During developmental angiogenesis, a mechanism by which astrocytes perform vascular guidance by means of VEGF-A was identified. The angiogenic sprout consists of two different endothelial cell populations: the tip-cell and stalk-cells. VEGF-A becomes deposited in a gradient like fashion at the front of the angiogenic sprout. This distribution is crucial for physiological vascular patterning, since it coordinates directed migration of tip-cells and proliferation by stalk cells. This concept was applied to a situation of pathological vascular patterning, i.e. the ischemic retina. We found that defective patterning is caused by disruption of VEGF-A gradients, where VEGF-A is liberated from the matrix by proteolytic enzymes, since inhibition of the activity of matrix-metalloproteases restores physiological vascular patterning.