Table 2.
New or age-related angiogenesis and vascular remodeling-related genes after stroke verified by RT-PCR.
| Sequence code | Gene symbol | Function | Young 3 days | Young 14 days | EP | Aged 3 days | Aged 14 days | EP | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| FC | SD | FC | SD | FC | SD | FC | SD | |||||
| INFLAMMATION-INDUCED VASCULAR REMODELING | ||||||||||||
| 10872361 | Bai2 | De novo angiogenesis inhibitor | −2.9 | 0.23 | 1.33 | 0.01 | −2.70 | 0.14 | −1.34 | 0.11 | ||
| 10736697 | Ccl2* | EC; monocyte chemoattractant protein; angiogenic | 23.3 | 1.56 | 5.72 | 0.5 | D | 20.9 | 0.56 | 7.72 | 0.33 | D |
| 10771655 | Cxcl10 | Leukocyte recruitment via Tnfa signaling | 2.90 | 0.51 | 6.36 | 0.43 | D | 3.65 | 0.09 | 9.00 | 1.1 | D |
| 10858165 | Cxcl12 | Chemoattractant, EPCs and SMC; promotes angiogenesis | 2.07 | 0.21 | 3.06 | 0.17 | A | 2.81 | 0.15 | 6.15 | 0.35 | A |
| 10767373 | Cxcr4 | Chemoattractant EPC; promotes angiogenesis | 13.7 | 0,22 | 3.81 | 0.54 | D | 9.37 | 0.33 | 4.68 | 0.28 | D |
| 10908896 | Ets1* | TF, early stage; neovascularization | 4.3 | 0.05 | 2.33 | 0.22 | D | 6.10 | 1.14 | 2.72 | 0.29 | D |
| 10907913 | Mmp8 | Macrophage collagenase; BM remodeling via Tnfa | 6.3 | 0.1 | 3.34 | 0.09 | D | 4.34 | 0.14 | 8.01 | 0.34 | A |
| 10907869 | Mmp12* | Fibroblasts collagenase (COL1) | 12.3 | 0.23 | 3.54 | 0.1 | B | 14.0 | 0.45 | 7.59 | 0.33 | D |
| 10780205 | Mmp14* | Collagenase; BL remodeling | 4.7 | 0.46 | 5.07 | 0.70 | A | 7.72 | 0,90 | 11.2 | 0,59 | A |
| 10714103 | Mpeg1 | Inflammatory mediator; macrophages | 4.6 | 0.31 | 4.15 | 0.34 | A | 3.90 | 0.22 | 9.14 | 0.44 | C |
| 10858967 | Tnfrsf1a | Inflammatory mediator; apoptosis | 3.2 | 0.02 | 3.33 | 0.04 | A | 3.78 | 0.17 | 6.29 | 0.07 | A |
| 10881424 | Tnfrsf1b | Attenuates inflammation | 4.6 | 0.25 | 4.16 | 0.20 | A | 4.41 | 0.14 | 8.28 | 0.10 | A |
| SPROUTING ANGIOGENESIS | ||||||||||||
| 10789291 | Angpt2 | Promotes the dissociation of pericytes | 8.2 | 0.48 | 3.55 | 0.19 | D | 4.37 | 0.48 | 7.17 | 0.27 | A |
| 10835654 | Angptl2 | Macrophages; pro-angiogenic | 4,3 | 0.21 | 3.32 | 0.15 | A | 2.44 | 0.11 | 3.99 | 0.2 | A |
| 10901166 | Angptl4 | EC; pro-angiogenic | 4.5 | 0.2 | 1.90 | 0.24 | B | 2.48 | 0.4 | 8.51 | 0.02 | A |
| 10723032 | Cib1* | Modulator of EC proliferation and migration | 7.8 | 0.78 | 1.69 | 0.09 | B | 3.46 | 0.14 | 8.01 | 0.00 | A |
| 10750685 | Col8a1 | VSMC; fibroblasts and SMC proliferation via Tgfb | 16.3 | 0.26 | 1.60 | 0.2 | B | 12.70 | 1.58 | 8.05 | 0.88 | D |
| 10914614 | Ccr2* | Chemoattractant EPC; promotes angiogenesis | 4.1 | 0.19 | 1.49 | 0.07 | B | 2.28 | 0.09 | 2.48 | 0.11 | A |
| 10775900 | Cxcl1 | Chemoattractant EPC; promotes angiogenesis | 95. | 6.77 | 8.25 | 1.97 | D | 22.0 | 4.16 | 19.1 | 1.15 | A |
| 10940663 | Eng** | EC; pro-angiogenic via TGFb signaling | 5.6 | 0.19 | 1.84 | 0.15 | B | 3.24 | 0.14 | 6.20 | 0.14 | A |
| 10715100 | Hhex** | TF; promotes vasculogenesis via VEGF | 6.1 | 0.32 | 2.29 | 0.26 | D | 4.29 | 0.27 | 3.12 | 0.07 | D |
| 10907689 | Itga5 | BV stabilization | 3.6 | 0.22 | 1.60 | 0.06 | B | 2.88 | 0.11 | 1.90 | 0.09 | B |
| 10819052 | Lef1 | EC proliferation and migration | 4.1 | 0.49 | 1.60 | 0.13 | B | 2.19 | 0.06 | 2.38 | 0.05 | A |
| 10808959 | Nrp1 | 2.5 | 0.48 | 1.33 | 0.22 | NC | 2.81 | 0.26 | 5.72 | 1.02 | A | |
| 10940659 | Pecam1 | EC marker; angiogenesis | 5.5 | 0.48 | 1.65 | 0.08 | B | 2.89 | 0.18 | 3.38 | 0.21 | A |
| 10832299 | Pttg1ip | EC proliferation and migration | 6.4 | 0.45 | 2.59 | 0.27 | D | 4.28 | 0.25 | 2.90 | 0.11 | D |
| 10905316 | Rac2 | EPC polarity and proliferation | 5.2 | 0.11 | 3.25 | 0.11 | A | 5.27 | 0.31 | 7.80 | 0.26 | A |
| 10753222 | Runx1 | EPC; pro-angiogenic | 3.3 | 0.21 | 2.30 | 0.17 | A | 2.15 | 0.44 | 4.63 | 0.2 | A |
| 10758645 | Sh2b3 | EC adhesion and migration | 4.0 | 0.32 | 2.23 | 0.16 | A | 3.78 | 0.28 | 2.65 | 0.5 | A |
| 10781022 | Sox7 | TF; arterial development; pro-angiogenic | 4.9 | 0.77 | 1.64 | 0.23 | B | 5.97 | 0.95 | 1.36 | 0.28 | B |
| 10797726 | Tpm3 | EC migration | 3.6 | 0.23 | 2.44 | 0.15 | A | 3.24 | 0.19 | 3.19 | 0.3 | A |
| 10790712 | Tpm4 | EC migration | 3.7 | 0.21 | 1.12 | 0.07 | B | 3.74 | 0.22 | 3.38 | 0.09 | A |
| 10751048 | Tagln | VSMC proliferation and differentiation | 10.8 | 0.58 | 1.82 | 0.23 | B | 21.1 | 0.49 | 2.21 | 0.17 | B |
| 10873021 | Wnt4 | VSMC proliferation and migration | 2.29 | 0.05 | 2.70 | 0.19 | A | 1.10 | 0.01 | 6.20 | 0.14 | C |
| RECONSTRUCTION OF BASAL LAMINA | ||||||||||||
| 10889339 | Adam17 | EC; ECM and vascular remodeling via Tnfa and Il6ra | 2.66 | 0.2 | 1.83 | 0.1 | B | 4.45 | 0.3 | 2.70 | 0.5 | A |
| 10792997 | Col4a2** | Reconstruction of a new BM | 23 | 1.34 | 1.49 | 0.01 | B | 5.36 | 0.5 | 3.41 | 0.01 | A |
| 10929766 | Col6a3 | Reconstruction of a new BM | 21.5 | 2.71 | 18.34 | 3.11 | A | 24.3 | 1.24 | 22.0 | 6.2 | A |
| 10928761 | Fn1 | BV stabilization | 4.5 | 0.23 | 2.39 | 0.2 | A | 3.32 | 0.3 | 3.69 | 0.45 | A |
| 10768668 | Lamc1 | Reconstruction of a new BM | 4.6 | 0.09 | 1.77 | 0.13 | B | 1.57 | 0.14 | 4.27 | 0.02 | C |
| 10782387 | Nid2 | Reconstruction of a new BM | 3.6 | 0.29 | 2.20 | 0.63 | A | 1.57 | 0.32 | 2.77 | 0.91 | C |
| 10912255 | Plod2** | Fibroblasts; collagen maturation; BM maturation | 3.8 | 0.22 | 1.80 | 0.05 | B | 1.57 | 0.03 | 3.66 | 0.08 | C |
| 10757461 | Plod3 | Reconstruction of a new BM via COL4 and COL6 | 2.0 | 0.20 | 2.29 | 0.12 | A | 2.80 | 0.11 | 1.65 | 0.01 | B |
| TUBE FORMATION AND BV MATURATION | ||||||||||||
| 10903529 | Angpt1 | PVC; BV maturation/stabilization | 2.7 | 0.51 | 3.78 | 0.61 | A | 2.48 | 0.4 | 8.51 | 0.61 | A |
| 10853559 | Col1a2 | Adventitial fibroblasts; aneurysms | 2.2 | 0.09 | 3.9 | 0.09 | A | 1.59 | 0.13 | 4.32 | 0.10 | C |
| 10891780 | Fbln5 | EC; vascular remodeling; BV elasticity | 10.7 | 1.5 | 2.03 | 0.03 | D | 8.66 | 0.5 | 2.60 | 0.15 | D |
| 10702913 | Fndc1 | BV stabilization | 1.34 | 0.15 | 3.94 | 0.17 | C | 1.13 | 0.09 | 3.91 | 0.11 | C |
| 10939764 | Gpc3* | Co-receptor for Fgf9; vascular development | 1.74 | 0.00 | 3.18 | 0.49 | A | 5.38 | 0.64 | 6.16 | 0.62 | A |
| 10772169 | Igfbp7 | Vascular remodeling; lumen formation | 1.79 | 0.13 | 2.84 | 0.10 | C | 1.49 | 0.06 | 4.37 | 0.45 | C |
| 10739721 | Itgb4 | Vascular integrity; BV maturation | 3.65 | 0.1 | 2.97 | 0.28 | A | 2.74 | 0.55 | 2.96 | 0.3 | A |
| 10817711 | Notch2 | Pro-angiogenic via VEGFR2 | 1.7 | 0.10 | 2.30 | 0.02 | C | 1.36 | 0.12 | 2.45 | 0.08 | C |
| 10760971 | Pcolce | Fibroblasts; vascular remodeling; lumen formation | 1.34 | 0.2 | 3.84 | 0.1 | C | 1.52 | 0.3 | 5.78 | 0.31 | C |
| 10802040 | Pdgfrb | Pericytes; BV stabilization | 2.24 | 0.04 | 2.26 | 0.06 | A | 1.68 | 0.10 | 2.95 | 0.10 | C |
| 10753222 | Runx3 | Negative regulator of EPC | 9.82 | 0.5 | 10.58 | 0.2 | A | 4.28 | 0.1 | 1.32 | 0.1 | B |
| 10746139 | Scpep1 | SMCs; elastogenesis and BV maturation | 7.78 | 0.01 | 7.04 | 0.61 | A | 8.17 | 0.62 | 6.09 | 0.27 | A |
| 10817057 | S100a4 | SMC proliferation and migration; aneurysms | 16.2 | 2.3 | 17.49 | 2.02 | A | 9.78 | 1.2 | 8.16 | 1.03 | A |
| 10742802 | SPARC** | Pericytes recruitment; BV stabilization | 1.97 | 0.12 | 4.84 | 0.51 | C | 2.49 | 0.13 | 8.42 | 0.55 | C |
| 10879278 | Tie1 | EC; modulates Angpt1/Tie2 signaling | 2.52 | 0.05 | 1.69 | 0.11 | B | 2.10 | 0.06 | 1.67 | 0.09 | B |
| 10869946 | Tie2 | Sprouting angiogenesis via Angpt2 | 8.23 | 0.48 | 3.55 | 0.19 | D | 4.17 | 0.48 | 7.17 | 0.27 | A |
| 10814528 | Tnfsf10 | EC; pro-apoptotic | 1.80 | 0.20 | 2.37 | 0.16 | C | −1.15 | 0.40 | 9.01 | 0.22 | C |
| Vegfc | 1.05 | 0.13 | 2.99 | 0.2 | C | 1.66 | 0.23 | 1.14 | 0.11 | NC | ||
| 10921772 | Vegfa** | Sprouting angiogenesi and tube formation | 1.15 | 0.09 | 2.40 | 0.07 | C | 1.34 | 0.22 | 1.09 | 0.05 | NC |
| BUILDUP OF FIBROTIC TISSUE | ||||||||||||
| 10737532 | Col1a1 | Fibrotic scar via Tgfb; aneurysm | 6.7 | 0.65 | 16.88 | 0.78 | C | 10.5 | 1.41 | 45.4 | 1.06 | C |
| 10923052 | Col3a1 | Adventitial fibroblasts; aneurysms | 16.0 | 0.91 | 57.82 | 0.32 | C | 32.8 | 2.44 | 237 | 7.44 | C |
| 10896263 | Cthrc1* | Fibroblasts and SMC; fibrosis via Tgfb | 13.0 | 1.47 | 1.80 | 0.02 | B | 11.4 | 0.22 | 10.8 | 1.46 | A |
| 10824530 | Il6ra* | Promotes vascular leakage | 1.90 | 0.15 | 1.90 | 0.60 | NC | 1.58 | 0.66 | 3.55 | 0.52 | C |
| 10813007 | Il6st | Promotes vascular leakage | 1.73 | 0.08 | 2.91 | 0.11 | C | 1.43 | 0.12 | 3.34 | 0.23 | C |
| 10754983 | Il13ra1 | Inhibits MMP secretion by fibroblasts; fibrosis | 3.76 | 0.17 | 3.14 | 0.12 | A | 3.3 | 0.20 | 6.73 | 0.21 | A |
| 10909874 | Il18 | Microglia; pro-fibrotic via fibroblasts proliferation | 4.17 | 0.24 | 1.77 | 0.04 | B | 3.66 | 0.22 | 7.59 | 0.44 | C |
| 10809540 | Mmp2 | Fibroblasts to myofibroblasts conversion | 2.88 | 0.32 | 2.7 | 0.62 | A | 5.08 | 1.02 | 14.5 | 6.41 | A |
| 10749663 | P4hb | Fibroblasts; collagen synthesis; fibrosis | 2.34 | 0.29 | 2.08 | 0.07 | A | 2.39 | 0.66 | 2.84 | 0.19 | A |
| 10776459 | Pdgfra | Fibrosis via TNFalpha and TGFbeta | 1.74 | 0.05 | 2.06 | 0.03 | C | 1.38 | 0.02 | 3.15 | 0.03 | C |
| 10864874 | Rassf4 | Mesenchymal cells; fibrosis | 6.25 | 0.1 | 12.24 | 1.46 | A | 4.73 | 0.86 | 23.3 | 2.9 | C |
| 10927842 | Stat1 | Promotes vascular leakage via Il6r | 2.01 | 0.01 | 2.55 | 0.02 | A | 1.57 | 0.05 | 3.53 | 0.09 | C |
| 10893067 | Stat2 | Promotes vascular leakage via Il6r | 1.59 | 0.04 | 1.67 | 0.06 | NC | 1.37 | 0.02 | 2.48 | 0.12 | C |
| 10868923 | Tgfbr1 | Fibroblasts and SMA proliferation; fibrosis | 8.29 | 1.11 | 14.15 | 0.66 | A | 9.39 | 0.81 | 12.1 | 0.09 | A |
| 10920745 | Tgfbr2* | Fibroblasts, SMC proliferation; fibrosis | 5.06 | 0.44 | 3.80 | 0.40 | A | 6.87 | 0.71 | 10.1 | 0.46 | A |
| 10705213 | Tgfb1 | Fibroblasts and SMA proliferation; fibrosis | 6.64 | 0.78 | 16.57 | 0.81 | C | 5.97 | 0.36 | 58.8 | 0.78 | C |
| 10797138 | Tgfbi | Fibroblasts and SMA proliferation; inhibition | 3.30 | 0.21 | 1.41 | 0.08 | B | 1.27 | 0.12 | 1.57 | 0.13 | NC |
| 10865094 | Wnt5b | EC proliferation and migration | 1.39 | 0.13 | 3.29 | 0.28 | C | 3.13 | 1.27 | 5.10 | 0.73 | A |
| 10936482 | Timp1 | Inhibits MMPs | 40.6 | 2.34 | 8.53 | 1.11 | D | 41.5 | 3.64 | 31.1 | 1.18 | A |
| LEGEND | *Confirmatory age effect | **Confirmatory age effect | |||||
| New genes for stroke | Aged-specific 3 days | Aged-specific 14 days | Young-specific, 3 days | Young-specific, 14 days |
There were several distinct patterns of gene regulation: persistently upregulated (A), transiently upregulated, (B), “late-upregulated” (C), or “late-downregulated” (D). Aged animals showed larger numbers of genes that were late-upregulated (type C). The young rats, in contrast, had a much larger number of transiently upregulated (type B). Note that this representation does not take into account the fold changes for individual genes but the relative change in gene expression at days 3 and 14 post-stroke. FC, fold change; SD, standard deviation; EP, expression pattern; NC, no change; TF, transcription factor; EC, endothelial cell; BV, blood vessel; VSMC, vascular smooth muscle cell; PVC, perivascular cells; BL, basal lamina; ECM, extracellular matrix.