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Age and exercise effects on brain angiogenic pathway and inflammatory factors
目的：研究一為分析大腦組織中血管新生機制於兩週運動訓練過程的變化；研究二為觀察單次運動對於高齡大腦血管新生機制之影響；研究三為觀察兩週運動訓練對於大腦血管新生機制之影響。方法：研究一使用3個月齡之雄性SD鼠，進行兩週且每天90分鐘的運動，收集動作皮層和海馬回組織的時間包括運動前(n=6)以及運動第1天(n=6)、第7天(n=6)和第14天(n=6)後一小時。研究二將使用3個月和12個月齡之雄性SD鼠，分為年輕控制組(YC，n=6)、年輕運動組(YE，n=6)、老年控制組(OC，n=6)和老年運動組(OE，n=6)，並於90分鐘單次游泳運動後1小時進行組織收集。研究三進行長期運動訓練，以與研究二相同的組別設計於兩週游泳運動後隔天收集組織。分析指標包括微血管密度、血管內皮生長因子(VEGF)、VEGF接受器-2 (Flk-1)、VEGF接受器-1 (Flt-1)、angiopoietin-1 (Ang1)和angiopoietin-2 (Ang 2)與Tie2、eNOS、糖化產物接受器(RAGE)、巨噬細胞標的蛋白(CD68)、超氧化物歧化酶(SOD1)以及第1類型葡萄糖轉運蛋白(GLUT1)之表現量。結果：研究一發現動作皮層區VEGF、Ang1和eNOS於運動第1天顯著增加後便回復至運動前水準，其接受器Flt-1和Tie2則分別於運動第1和7天後顯著增加並持續至第14天，而CD68於運動第1至14天均顯著增加，動作皮層區之微血管密度於運動第7天顯著減少而第14天又回升；海馬回區之VEGF、Flt-1和Ang1 以及CD68、SOD1和GLUT1於運動第1天期間內顯著增加後便回復至運動前水準，海馬回之微血管密度於兩週運動期間無顯著變化。研究二發現OC組動作皮層區及海馬回區之SOD1均顯著高於YC組，且僅OC組動作皮層區之Flk-1 mRNA以及Flt-1、eNOS、Ang1和CD68蛋白表現均顯著高於YC組，而這些差異並無出現於海馬回；OE組與OC組之血管新生因子和發炎指標均無顯著差異。研究三發現兩週運動後，YE組之兩腦區血管新生因子和發炎指標與YC組多無顯著差異，OE與OC組之比較亦獲得相同結果，僅YE組和OC組動作皮層之CD68均顯著高於YC組，以及OE組海馬回之CD68顯著高於OC組；YE組於動作皮層和海馬回之微血管密度均顯著高於YC組，OE組之CD31呈色亦有高於OC組之趨勢，而OC組的AP和CD31呈色均顯著低於YC組僅出現於海馬回區域。結論：本研究顯示兩週且每日90分鐘之游泳運動有助於腦部血管網路的汰換，且海馬回的血管新生因子相較於動作皮層區具有較快的調適反應，然海馬回區域相較於動作皮層區提早出現血管網路的退化，而兩週游泳運動訓練可引致年輕腦部之血管新生，亦可能對於中老年腦部血管結構具正面效應。|
Abstract Purposes: Study I was to examine the time-course changes in brain angiogenic mechanism during 2-week exercise; study II to determine acute exercise effect on brain angiogenic mechanism for the middle-aged; and study III to investigate the effect of 2-week exercise on brain angiogenic mechanism. Methods: Study I recruited 3 months old male SD rats to 14-day swimming exercise for 90 minutes/day. Tissues from motor cortex and hippocampus were collected pre-exercise (n=6) and after 1 hour post-exercise at day 1(n=6), day 7 (n=6) and day 14 (n=6). Study II assigned 3 and 12 months old male SD rats to young control (YC, n=6), young exercise (YE, n=6), old control (OC, n=6) and old exercise (OE, n=6) groups. Tissues were collected within 1 hour after one single-bout swimming for 90 minutes. Study III included the same group design as Study II and tissues were collected on the next day after 2-week swimming program. Measurements included capillary density, the expression of vascular endothelial growth factor (VEGF), VEGF receptor-2 (Flk-1), VEGF receptor-1 (Flt-1), angiopoietin-1 (Ang1), angiopoietin-2 (Ang2), Tie2, eNOS, receptor for AGE (RAGE), macrophage marker (CD68), superoxide dismutae (SOD1) and glucose transportor-1 (GLUT1). Results: Study I founded that VEGF, Ang1 and eNOS expression were significantly higher post exercise at day 1 and then returned to pre-exercise level. Their receptors were significantly higher post exercise at day 1 or 7 and then remained to day 14. CD68 was significantly higher post exercise during day 1 to 14. Capillary density in motor cortex was significantly lower post exercise at day 7 and then returned at day 14. For hippocampus, VEGF, Flt-1 and Ang1as well as SOD1, CD68 and GLUT1 were significantly higher post exercise at day 1 and then returned to pre-exercise level. No significant changes in capillary density were noted in hippocampus during 2-week exercise. Study II founded that significantly higher SOD1 was noted in OC motor cortex and hippocampus than YC. Also, higher Flk-1 mRNA and the protein expression of Flt-1, eNOS, Ang1 and CD68 were noted only in OC motor cortex than YC but not hippocampus. No significantly difference of angiogenic and inflammatory factors was noted between OE and OC. Study III denoted that no significantly difference of most angiogenic and inflammatory factors in both brain areas was found between YE and YC after 2-week exercise. The same results came to the comparison between OE and OC. Only significantly greater CD68 was founded in YE and OC motor cortex comparing to YC as well as in OE hippocampus comparing to OC. Further, capillary density in YE motor cortex and hippocampus were significantly higher than YC. Meanwhile, CD31-positive stain tended to be higher in OE than OC. Only for hippocampus, both AP and CD31-positive stains were significantly lower in OC comparing to YC. Conclusions: These findings suggested that 2-week swimming exercise with 90 minutes per day may cause turnover in vascular network. Angiogenic factors in hippocampus had rapid adaptation rather than motor cortex in response to exercise, while the early onset of degeneration in vascular network was noted in hippocampus prior to motor cortex. Additionally, 2-week swimming exercise can enhance angiogenesis for young brain and might have positive effect on vascular structure for middle-aged.
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