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.

Aim Adult neurogenesis occurs in two major niches in the brain: the subgranular zone of the hippocampal formation and the ventricular‐subventricular zone. Neurogenesis in both niches is reduced in ageing and neurological disease involving dementia. Exercise can rescue memory by enhancing hippocampal neurogenesis, but whether exercise affects adult neurogenesis in the ventricular‐subventricular zone remains unresolved. Previously, we reported that exercise induces angiogenesis through activation of the lactate receptor HCA1. The aim of the present study is to investigate HCA1‐dependent effects on neurogenesis in the two main neurogenic niches. Methods Wild‐type and HCA1 knock‐out mice received high intensity interval exercise, subcutaneous injections of L‐lactate, or saline injections, five days per week for seven weeks. Well‐established markers for proliferating cells (Ki‐67) and immature neurons (doublecortin), were used to investigate neurogenesis in the subgranular zone and the ventricular‐subventricular zone. Results We demonstrated that neurogenesis in the ventricular‐subventricular zone is enhanced by HCA1 activation: Treatment with exercise or lactate resulted in increased neurogenesis in wild‐type, but not in HCA1 knock‐out mice. In the subgranular zone, neurogenesis was induced by exercise in both genotypes, but unaffected by lactate treatment. Conclusion Our study demonstrates that neurogenesis in the two main neurogenic niches in the brain is regulated differently: Neurogenesis in both niches was induced by exercise, but only in the ventricular‐subventricular zone was neurogenesis induced by lactate through HCA1 activation. This opens for a role of HCA1 in the physiological control of neurogenesis, and potentially in counteracting age‐related cognitive decline.

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SUMMARYHooded seals (Cystophora cristata) rely on large stores of oxygen, either bound to hemoglobin or myoglobin (Mb), to support prolonged diving activity. Pups are born with fully developed hemoglobin stores, but their Mb levels are only 25-30% of adult levels. We measured changes in muscle [Mb] from birth to 1year of age in two groups of captive hooded seal pups, one being maintained in a seawater pool and one on land during the first 2months. All pups fasted during the first month, but were fed from then on. The [Mb] of the swimming muscle musculus longissimus dorsi (LD) doubled during the month of fasting in the pool group. These animals had significantly higher levels and a more rapid rise in LD [Mb] than those kept on land. The [Mb] of the shoulder muscle, m. supraspinatus, which is less active in both swimming and hauled-out animals, was consistently lower than in the LD and did not differ between groups. This suggests that a major part of the postnatal rise in LD [Mb] is triggered by (swimming) activity, and this coincides with the previously reported rapid early development of diving capacity in wild hooded seal pups. Liver iron concentration, as determined from another 25 hooded seals of various ages, was almost 10 times higher in young pups (1-34days) than in yearling animals and adults, and liver iron content of pups dropped during the first month, implying that liver iron stores support the rapid initial rise in [Mb].

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