International Journal of Molecular Sciences Review The Janus Face of VEGF in Stroke Samuel J. Geiseler 1 and Cecilie Morland 1,2, * 1 Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, 0371 Oslo, Norway; samuel.geiseler@farmasi.uio.no 2 Institute for Behavioral Sciences, Faculty of Health Sciences, OsloMet—Oslo Metropolitan University, 0166 Oslo, Norway * Correspondence: cecilie.morland@farmasi.uio.no; Tel.: +47-22-844-937 Received: 28 March 2018; Accepted: 1 May 2018; Published: 4 May 2018   Abstract: The family of vascular endothelial growth factors (VEGFs) are known for their regulation of vascularization. In the brain, VEGFs are important regulators of angiogenesis, neuroprotection and neurogenesis. Dysregulation of VEGFs is involved in a large number of neurodegenerative diseases and acute neurological insults, including stroke. Stroke is the main cause of acquired disabilities, and normally results from an occlusion of a cerebral artery or a hemorrhage, both leading to focal ischemia. Neurons in the ischemic core rapidly undergo necrosis. Cells in the penumbra are exposed to ischemia, but may be rescued if adequate perfusion is restored in time. The neuroprotective and angiogenic effects of VEGFs would theoretically make VEGFs ideal candidates for drug therapy in stroke. However, contradictory to what one might expect, endogenously upregulated levels of VEGF as well as the administration of exogenous VEGF is detrimental in acute stroke. This is probably due to VEGF-mediated blood–brain-barrier breakdown and vascular leakage, leading to edema and increased intracranial pressure as well as neuroinflammation. The key to understanding this Janus face of VEGF function in stroke may lie in the timing; the harmful effect of VEGFs on vessel integrity is transient, as both VEGF preconditioning and increased VEGF after the acute phase has a neuroprotective effect. The present review discusses the multifaceted action of VEGFs in stroke prevention and therapy. Keywords: growth factor; VEGF; stroke; ischemia; exercise 1. Introduction Millions of people suffer a stroke every year, and stroke is the main cause of disabilities among adults. The two major causes of stroke are an occlusion of a precerebral or cerebral artery or a hemorrhage. Both cause ischemia, which rapidly leads to necrosis in the stroke core. The fate of the area surrounding the necrotic core, the penumbra, depends largely on the time before reperfusion is restored. Neural death is proportional to the degree of loss in perfusion, and early reperfusion is essential to prevent extensive neural damage [1–4]. Brain injury after stroke occurs as a result of a complex series of pathophysiological events, including excitotoxicity, oxidative stress, vasopermeability of the blood–brain barrier (BBB), and inflammation, leading to cell death. Growth factors are important regulators of protection and recovery after ischemia, and the combined action of growth factors regulates angiogenesis, neuroprotection, neurogenesis as well as the migration of neuronal stem cells into the ischemic area, and their proliferation into functional neurons. One important family of growth factors is the family of vascular endothelial growth factors (VEGFs). Due to their upregulation in the ischemic brain and their strong angiogenic and neuroprotective properties [5–9], the administration of VEGFs per se, or substances that regulate VEGFs or VEGF receptor actions, are considered interesting potential treatment strategies in stroke. Int. J. Mol. Sci. 2018, 19, 1362; doi:10.3390/ijms19051362 www.mdpi.com/journal/ijms