phorbol-12-13-didecanoate and Stroke

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, 4α-phorbol 12,13-didecanoate (4α-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

Topics: Animals; Brain Ischemia; Cell Movement; Cell Proliferation; Ion Channel Gating; Microvessels; Neovascularization, Physiologic; Neural Stem Cells; Neurogenesis; Nitric Oxide Synthase Type III; Phorbol Esters; Rats, Sprague-Dawley; Recovery of Function; RNA, Messenger; Stroke; TRPV Cation Channels; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2