Research ReportCoupling of neurogenesis and angiogenesis after ischemic stroke
Introduction
Stroke is a leading cause of mortality and severe disability worldwide. Currently, the number of patients suffering from stroke is steadily increasing. The only proven therapy for acute ischemic stroke approved by the FDA is systemic thrombolysis with recombinant tissue plasminogen activator (rtPA). However, it must be administered within 4.5 h after the onset of stroke for rtPA to be effective. As a result, the short therapeutic time window and the potential complication from intracranial hemorrhage benefit only a minority of stroke patients (Zhang and Chopp, 2009). Even with successful rtPA thrombolysis, most stroke survivors still suffer from permanent neurological functional deficits. Therefore, extending the therapeutic time window of rtPA or uncovering new therapeutic strategies for the treatment of ischemic stroke is highly sought after.
In the past decade, several independent research groups have reported that neurogenesis continues into adulthood (Wang and Jin, 2014). Neurogenesis is the process of producing new functional neurons from neural stem/progenitor cells (NSCs), including proliferation of endogenous NSCs, migration, and differentiation into mature functional neurons. It is well accepted now that neurogenesis occurs at two distinct regions in the intact brain throughout life: the subventricular zone (SVZ) of the lateral ventricles and subgranular zone (SGZ) in the dentate gyrus of the hippocampus (Wang and Jin, 2014). In pathological conditions such as ischemic stroke, enhanced neurogenesis has been reported in animal models of stroke and even in stroke patients (Jin et al., 2001, Jin et al., 2006, Thored et al., 2006), suggesting a potential avenue for the treatment of ischemic stroke. However, it is now apparent that neurogenesis is not the stand-alone consideration in the fight for full functional recovery from stroke. One should now also factor in the role of angiogenesis as it has been shown to be critical in improving post-stroke neurological functional recovery.
Angiogenesis, defined as new microvessel formation via branching off from pre-existing vessels (Carmeliet and Jain, 2011), is a multi-step biological process, including proliferation and sprouting of endothelial cells, formation of tube-like vascular structures, branching and anastomosis (Risau, 1997). Angiogenesis is found in the penumbra of the brain infarct region in animal models of stroke and even in the brains of stroke patients (Hayashi et al., 2003, Krupinski et al., 1994, Zhang et al., 2002). It has been reported that neurogenesis and angiogenesis occur in the brains of stroke patients and a positive correlation was seen between patient survival and density of microvessels (Krupinski et al., 1994). Several findings in addition to this prove that neurogenesis and angiogenesis are coupled processes after an insult such as ischemic stroke, and should be acknowledged and pursued as concurrent and non-mutually exclusive events to further develop neurorestorative therapy.
This mini-review aims to establish the underlying mechanisms of how ischemic stroke induces endogenous neurogenesis and angiogenesis, and then address the interplay between neurogenesis and angiogenesis after ischemic stroke.
Section snippets
Mechanisms underlying stroke-induced neurogenesis
In the following sections, we review cellular and molecular mechanisms underlying stroke-induced neurogenesis and how factors released by endothelial cells may participate in the process.
Mechanisms underlying stroke-induced angiogenesis
New vessels are generated in the brain through several ways, including angiogenesis, vasculogenesis, and collateral vessel growth. The overarching purpose for the generation of these new vessels is to increase collateral circulation as first line defense against ischemia. Mounting evidence indicate that angiogenesis play a crucial role in ischemic stroke brain repair and long-term functional recovery. In animal models of ischemic stroke, proliferation of endothelial cells at 12–24 h after injury
Coupling between neurogenesis and angiogenesis after ischemic stroke
Recent evidence has shed more light on the role of the brain vasculature in neurogenesis (Lacar et al., 2012, Shen et al., 2008, Tavazoie et al., 2008). Capillaries in the SVZ are shown to be permeable to diffusible molecules released from endothelial cells such as VEGF (Jin et al., 2002), FGF-2 (Biro et al., 1994), amongst many others. This is possible because pericytes and astrocytic end feet do not tightly envelope the capillaries in the region of the SVZ, thereby creating a special
Conclusion
Ischemic stroke induces coordinated endogenous neurogenesis and angiogenesis, which contributes to brain repair. The potential mechanisms that trigger augmented endogenous neurogenesis and angiogenesis after stroke are becoming increasingly known. Ischemic stroke promotes the proliferation of NSCs by a variety of growth factors including FGF-2, IGF-1, BDNF, and VEGF. After NSC proliferation, neuroblasts migrate from the SVZ neurogenic niche to the injured brain region through the production of
Conflict of interest
The authors have no conflict of interests to declare.
Acknowledgments
This work is supported by the National Natural Science Foundation of China (81371396) to QZ, National Natural Science Foundation of China (81400954) to LR, and by the National Institute of Health (NIH) Grants AG21980 and NS057186 to KJ.
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These authors contributed equally to this work.