Transcriptomics of post-stroke angiogenesis in the aged brain

You will need to have your doctor translate this for you. Angiogenesis is creation of new blood vessels so your doctor had better know how to do this for your damaged brain.
http://journal.frontiersin.org/Journal/10.3389/fnagi.2014.00044/full?

Ana Maria Buga^1,2, Claudiu Margaritescu², Claus Juergen Scholz³, Eugen Radu⁴, Christine Zelenak⁵ and Aurel Popa-Wagner¹*

• 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

Despite the obvious clinical significance of post-stroke angiogenesis in aged subjects, a detailed transcriptomic analysis of post-stroke angiogenesis has not yet been undertaken in an aged experimental model. In this study, by combining stroke transcriptomics with immunohistochemistry in aged rats and post-stroke patients, we sought to identify an age-specific gene expression pattern that may characterize the angiogenic process after stroke. We found that both young and old infarcted rats initiated vigorous angiogenesis. However, the young rats had a higher vascular density by day 14 post-stroke. “New-for-stroke” genes that were linked to the increased vasculature density in young animals included Angpt2, Angptl2, Angptl4, Cib1, Ccr2, Col4a2, Cxcl1, Lef1, Hhex, Lamc1, Nid2, Pcam1, Plod2, Runx3, Scpep1, S100a4, Tgfbi, and Wnt4, which are required for sprouting angiogenesis, reconstruction of the basal lamina (BL), and the resolution phase. The vast majority of genes involved in sprouting angiogenesis (Angpt2, Angptl4, Cib1, Col8a1, Nrp1, Pcam1, Pttg1ip, Rac2, Runx1, Tnp4, Wnt4); reconstruction of a new BL (Col4a2, Lamc1, Plod2); or tube formation and maturation (Angpt1, Gpc3, Igfbp7, Sparc, Tie2, Tnfsf10), had however, a delayed upregulation in the aged rats. The angiogenic response in aged rats was further diminished by the persistent upregulation of “inflammatory” genes (Cxcl12, Mmp8, Mmp12, Mmp14, Mpeg1, Tnfrsf1a, Tnfrsf1b) and vigorous expression of genes required for the buildup of the fibrotic scar (Cthrc1, Il6ra, Il13ar1, Il18, Mmp2, Rassf4, Tgfb1, Tgfbr2, Timp1). Beyond this barrier, angiogenesis in the aged brains was similar to that in young brains. We also found that the aged human brain is capable of mounting a vigorous angiogenic response after stroke, which most likely reflects the remaining brain plasticity of the aged brain.

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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