Poststroke angiogenesis, con: dark side of angiogenesis.

A ngiogenesis, the regrowth of new blood vessels, occurs after stroke 1 and thus raises hopes that this regeneration is beneficial for patients with stroke. There is no doubt, that the restoration of blood supply, providing oxygen and nutrients to the ischemic brain tissue, is beneficial for stroke recovery. However, it is debated, whether angiogenesis truly contributes to improved recovery. Thus, fully functional new vessels occur only after several days, 2 as angiogenesis is a multistep process. It is, therefore, important to have a close look at the angiogenic dynamics itself and to critically assess some pathophysiologic steps, which can be even aggravating stroke progression. Angiogenic cues arise from periods of hypoxia. Vascular endothelial growth factor (VEGF) is the most potent trigger for inducing angiogenesis and shows high upregulation as early as 1 hour after stroke. Unfortunately, it also regulates vascular permeability. 3 Consequently, studies using VEGF delivery as a treatment for enhancing poststroke angiogenesis revealed not only positive effects but also negative effects. The therapeutic stimulation of angiogenesis with VEGF is clearly dependent on the route and timing of administration. In general, local and subacute administration is better tolerated than systemic and acute delivery. 4 Intravenous administration of VEGF early after stroke to speed up blood supply improvement led to blood brain–barrier leakage and, in consequence, aggravated vasogenic edema and increased infarct volume. Investigations of VEGF-induced blood brain–barrier leakage revealed that blocking VEGF after hypoxia or ischemia reduces vascular leakage, brain edema, and even infarct volume. For new vessels to evolve the parenchyma needs to reorganize , that is, making space and providing structures for vessel formation. Matrix metalloproteinases (MMPs) are involved in the degradation and remodelling of the extracellular matrix. Thus, MMPs play an important role in the initial steps of angiogenesis as they degrade the basal lamina for endothe-lial cell invasion. Unfortunately, this process is a further factor contributing to poststroke edema formation. Blockage of MMP activity has indeed been reported to reduce edema formation showing beneficial effects for stroke outcome. A further pathophysiologic event to be considered in association with angiogenesis also stems from leaky vessels. The degradation of the extracellular matrix during angiogenesis has been correlated with high levels of MMPs, in particular upregulation of MMP-2 and MMP-9. 5 But such high levels of MMPs correlate with the event of hemorrhagic transformation after tissue-type plasminogen activator treatment. 6 Such increased risk for hemorrhagic transformation has …