Abstract
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.
Highlights
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
By comparative transcriptomics of angiogenesis, we identified 36 new stroke-related genes some of which may be used as new therapeutic targets that may help redress the dysregulation of angiogenesis in the infarcted area of aged brain
We 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
Summary
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. Impaired neovascularization was described in elderly, but the effect of aging on angiogenesis and vascular remodeling after stroke has not been studied in detail. 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. 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). Currently there is no effective and safe stem cell-based therapy for stroke (Lees et al, 2012)
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