阿尔茨海默病（AD）和与阿尔茨海默病相关的痴呆（ADRD）是神经退行性疾病。最近的研究提示，脑低灌注是AD/ADRD的早期症状。双特异性蛋白磷酸酶5（DUSP5）已被认为参与了多种病理条件，包括肺动脉高压和癌症，但其在AD/ADRD中的作用尚不清楚。本研究基于我们先前的发现，表明抑制ERK和PKC导致剂量依赖性扩张中脑动脉和穿透小动脉，Dusp5 KO大鼠中的效应更明显。ERK和PKC抑制剂都显著降低了Dusp5 KO大鼠血管的肌原性张力。Dusp5 KO大鼠在表层但不是深层皮层脑血流自动调节上表现较强。ERK和PKC的抑制显著增强了两株细胞系血管平滑肌细胞的收缩能力。最后，在初步训练后24小时，观察到Dusp5 KO大鼠学习和记忆的显著改善。我们的结果表明，Dusp5 KO大鼠中的血管反应性变化可能涉及不同血管床的不同机制，而DUSP5缺失可能是AD/ADRD潜在的治疗靶点。进一步的研究有必要确定DUSP5抑制对毛细血管阻滞、血脑屏障通透性和衰老和疾病模型中的神经退行性的影响。

Alzheimer's Disease (AD) and Alzheimer's Disease-Related Dementias (ADRD) are neurodegenerative disorders. Recent studies suggest that cerebral hypoperfusion is an early symptom of AD/ADRD. Dual-specificity protein phosphatase 5 (DUSP5) has been implicated in several pathological conditions, including pulmonary hypertension and cancer, but its role in AD/ADRD remains unclear. The present study builds on our previous findings, demonstrating that inhibition of ERK and PKC leads to a dose-dependent dilation of the middle cerebral artery and penetrating arteriole, with a more pronounced effect in Dusp5 KO rats. Both ERK and PKC inhibitors resulted in a significant reduction of myogenic tone in vessels from Dusp5 KO rats. Dusp5 KO rats exhibited stronger autoregulation of the surface but not deep cortical cerebral blood flow. Inhibition of ERK and PKC significantly enhanced the contractile capacity of vascular smooth muscle cells from both strains. Finally, a significant improvement in learning and memory was observed in Dusp5 KO rats 24 hours after initial training. Our results suggest that altered vascular reactivity in Dusp5 KO rats may involve distinct mechanisms for different vascular beds, and DUSP5 deletion could be a potential therapeutic target for AD/ADRD. Further investigations are necessary to determine the effects of DUSP5 inhibition on capillary stalling, blood-brain barrier permeability, and neurodegeneration in aging and disease models.