http://journal.frontiersin.org/Journal/10.3389/fnagi.2014.00044/full?
- 1Department of Psychiatry, University of Medicine Rostock, Rostock, Germany
- 2Center of Clinical and Experimental Medicine, University of Medicine Craiova, Craiova, Romania
- 3IZKF Lab for Microarray Applications, University of Würzburg, Würzburg, Germany
- 4University of Medicine and Pharmacy Carol Davila, Bucharest, Romania
- 5Molecular Oncology, Department of Medicine, Lady Davis Institute for Medical Research, McGill University, Montreal, QC, Canada
Introduction
Recuperative therapeutic strategies for stroke are
focused on revascularization, neuroprotection, and neuroregeneration,
but most of the strategies that have been clinically tested failed to
show benefit in humans. Post-stroke vascular remodeling is an essential
event with crucial importance for neuroregeneration but unfortunately
this process is still incompletely understood and therefore not
exploited for therapeutic purposes (Masuda and Asahara, 2003; Hayashi et al., 2006; Caiado and Dias, 2012; Liman and Endres, 2012).
Aging is one of the most important risk factors for stroke (Barnett, 2002).
Impaired neovascularization was described in elderly, but the effect of
aging on angiogenesis and vascular remodeling after stroke has not been
studied in detail. Previous studies from our group showed that,
following insult to the brain, old rats are still capable of
upregulating genes that are active during development, but the response
is often blunted and temporarily uncoordinated (Buga et al., 2008).
Understanding mechanisms underlying angiogenesis and
vascular remodeling after stroke in the elderly is crucial for
developing new treatment strategies to improve the functional outcome
after stroke in aged patients. Unfortunately, the molecular mechanisms
regulating angiogenesis and vascular remodeling in aging brains are
still poorly understood. Endothelial progenitor cells (EPCs) are likely
to promote vasculogenesis after cerebral ischemia. Therefore, the
regenerative potential of EPCs has been under intense investigation (Peichev et al., 2000).
Many angiogenic factors, such as VEGF, IGFs, or FGFs, are involved in
the mobilization of EPCs and increased levels of EPCs were correlated
with increased plasma VEGF levels in stroke patients (Rafii et al., 2002). However, currently there is no effective and safe stem cell-based therapy for stroke (Lees et al., 2012).
Other studies have established that bone
marrow-derived EPCs are present in the systemic circulation, and that
they are able to differentiate into mature endothelial cells (EC) in the
ischemic area, but the number of these cells is reduced by aging (Zhang et al., 2006; Mikirova et al., 2009).
Previously, we have shown that cytokine-induced generation of bone
marrow-derived EPCs can be enhanced by the administration of
granulocyte-colony stimulating factor (G-CSF), and leads to improved
functional outcome after stroke in aged rats (Popa-Wagner et al., 2010).
Few studies have investigated human post-stroke angiogenesis at the molecular level. Thus, Krupinski et al. (1994)
noted active angiogenesis in the penumbral areas of patients who
survived from several days to weeks after cerebral stroke, as well as a
positive correlation between microvessel density and patient survival.
In subsequent studies, the authors demonstrated an increased synthesis
of angiogenic growth factors such as FGF-2, platelet-derived growth
factor (PDGF), VEGF, and their receptors within hours of stroke that
correlated with blood vessel growth in the penumbra (Krupinski et al., 1996, 1997).
The literature on gene expression profiles after stroke in humans also is limited. In this regard, Vikman and Edvinsson (2006)
have shown similarities in gene expression profiles between human
strokes and those in animal models, and reported new genes that support
the dynamic changes that occur in the middle cerebral artery branches
supplying the ischemic region. Also, promising results of blood genomic
profiling in human stroke have been obtained in pilot studies (Moore et al., 2005; Tang et al., 2006; Tan et al., 2009).
These results argue for the utility of pro-angiogenic therapies in
stroke, given the potential effects consisting of increasing blood flow,
decreasing infarct size, and supporting the restoration and recovery of
neurovascular networks after ischemia (Liman and Endres, 2012).
Despite the obvious clinical significance of
post-stroke angiogenesis in aged subjects, a detailed analysis of
transcriptomics of post-stroke angiogenesis has not been done yet in an
aged experimental model. By combining stroke transcriptomics with
immunohistochemistry in aged rats and post-stroke patients, in this
study we aimed at (i) identifying an age-specific gene expression
pattern that may characterize the angiogenic process after stroke, (ii)
exploring the potential of older animals to initiate regenerative
processes following cerebral ischemia by supportive angiogenesis. This
approach should allow us to identify new therapeutic targets that are
crucial for enhancing neurorestoration after stroke in the elderly.
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