TRPV4 Activation Contributes Functional Recovery from Ischemic Stroke via Angiogenesis and Neurogenesis

被引:52
作者
Chen, Chun-Kai [1 ,2 ]
Hsu, Po-Yuan [3 ]
Wang, Tzu-Ming [3 ]
Miao, Zhi-Feng [4 ]
Lin, Ruey-Tay [5 ]
Juo, Suh-Hang H. [3 ,6 ,7 ,8 ,9 ]
机构
[1] Kaohsiung Med Univ Hosp, Dept Phys Med & Rehabil, Kaohsiung, Taiwan
[2] Kaohsiung Med Univ, Grad Inst Med, Collage Med, Kaohsiung, Taiwan
[3] China Med Univ Hosp, Dept Med Res, Taichung, Taiwan
[4] Kaohsiung Med Univ Hosp, Div Colorectal Surg, Dept Surg, Kaohsiung, Taiwan
[5] Kaohsiung Med Univ Hosp, Dept Neurol, Kaohsiung, Taiwan
[6] China Med Univ, Grad Inst Biomed Sci, Taichung, Taiwan
[7] China Med Univ, Inst New Drug Dev, Taichung, Taiwan
[8] China Med Univ, Brain Dis Res Ctr, Taichung, Taiwan
[9] China Med Univ, Ctr Myopia & Eye Dis, Taichung, Taiwan
关键词
TRPV4; Nitric oxide synthase; Angiogenesis; Neurogenesis; Ischemic stroke; NITRIC-OXIDE SYNTHASE; ENDOTHELIAL-CELLS; PROGENITOR CELLS; GROWTH-FACTOR; MECHANISMS; DISEASE; BRAIN; PROLIFERATION; RECEPTOR; EXPRESSION;
D O I
10.1007/s12035-017-0625-0
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The endothelial transient receptor potential cation channel subfamily V member 4 (TRPV4) plays a crucial role in vascular remodeling; however, TRPV4-mediated angiogenesis after ischemic neuronal death as a neurorestorative strategy has not yet been thoroughly examined. In this study, we first tested whether TRPV4 activation can improve functional recovery in rats subjected to transient brain ischemia. The possible mechanisms for TRPV4 activation-promoted functional recovery were explored. A TRPV4 agonist, 4 alpha-phorbol 12,13-didecanoate (4 alpha-PDD), was intravenously injected via the tail vein at 6 h and 1, 2, 3, 4 days after ischemic stroke. The treatment reduced infarct volume by almost 50% (14.7 +/- 3.7 vs. 29.2 +/- 6.2%; p < 0.0001) and improved functional outcomes (p = 0.03) on day 5. To explore the therapeutic mechanism, we measured endothelial nitric oxide synthase (eNOS) expression and phosphorylation, vascular endothelial growth factor A (VEGFA) signaling, and neural stem/progenitor cells (NPCs). TRPV4 activation significantly increased eNOS expression and phosphorylation (serine 1177) by more than 2-fold in the ischemic region. The expressions of VEGFA and VEGF receptor-2 were significantly higher in the treated animals, especially an increase of the proangiogenic VEGFA(164a) isoform while a decrease of the antiangiogenic VEGFA(165b) isoform. We evaluated angiogenesis by detecting microvessel density in ischemic region. Using the immunohistochemistry staining, we found that 4 alpha-PDD treatment caused a 3.4-fold increase of microvessel density (p < 0.0001). In addition, NPC proliferation and migration in the ischemic hemisphere were increased by 3-fold and 5-fold, respectively. In conclusion, our data suggest that TRPV4 activation by 4 alpha-PDD may improve poststroke functional improvement through angiogenesis and neurogenesis.
引用
收藏
页码:4127 / 4135
页数:9
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