Transcriptomics of Post-Stroke Angiogenesis in the Aged Brain

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.

Discrepancy in Expression of β-Secretase and Amyloid-β Protein Precursor in Alzheimer-Related Genes in the Rat Medial Temporal Lobe Cortex Following Transient Global Brain Ischemia

“…Probably early post-ischemic Alzheimer-related gene dysregulation triggers delayed gene dysfunction in post-stroke patients and old ischemic rats [57][58][59]. Buga et al [57][58][59] have identified an age-related gene expression pattern following brain ischemia.…”

“…Buga et al [57][58][59] have identified an age-related gene expression pattern following brain ischemia. These studies indicated that genes specific for anxiety, depression, stress, and neuropathic syndrome had harmful response to ischemia in aged rats.…”

Knockdown of angiopoietin like-2 protects against angiotensin II-induced cerebral endothelial dysfunction in mice

“…Mice were anesthetized and maintained throughout the procedure by inhalation of isoflurane (1-3% mixed with 97% O 2). For 3 wk before subcutaneous implantation, mice were trained by tail-cuff plethysmography (Kent Scientific, Torrington, CT) with baseline recording and during the 14 days of subcutaneous treatment, blood pressure (systolic, diastolic, and mean arterial pressures) and heart rate were noninvasively recorded on days 5,10,12, and 14 as previously described (3). For reference, blood pressure was also assessed under anesthesia by both Millar catheter and tail-cuff.…”

“…On the other hand, upregulation of angptl2 gene expression, among other genes, was recently reported in the aged brain of both rats and human, contributing to poststroke angiogenesis (5). Information of angptl2 involvement in regulating endothelial function, however, is limited.…”

Current Stage and Future Perspective of Stem Cell Therapy in Ischemic Stroke

“…Our studies before showed that the combination of G-CSF and BMSCs increased new blood vessel formation in the infarct core generating an "regeneration islet" [33]. However, BMSCs therapy needs further investigation.…”