PDF(Pubmed)
Abstract：
Functional hyperemia-activity-dependent increases in local blood perfusion-underlies the on-demand delivery of blood to regions of enhanced neuronal activity, a process that is crucial for brain health. Importantly, functional hyperemia deficits have been linked to multiple dementia risk factors, including aging, chronic hypertension, and cerebral small vessel disease (cSVD). We previously reported crippled functional hyperemia in a mouse model of genetic cSVD that was likely caused by depletion of phosphatidylinositol 4,5-bisphosphate (PIP2) in capillary endothelial cells (EC) downstream of impaired epidermal growth factor receptor (EGFR) signaling. Here, using EC-specific EGFR-knockout (KO) mice, we directly examined the role of endothelial EGFR signaling in functional hyperemia, assessed by measuring increases in cerebral blood flow in response to contralateral whisker stimulation using laser Doppler flowmetry. Molecular characterizations showed that EGFR expression was dramatically decreased in freshly isolated capillaries from EC-EGFR-KO mice, as expected. Notably, whisker stimulation-induced functional hyperemia was significantly impaired in these mice, an effect that was rescued by administration of PIP2, but not by the EGFR ligand, HB-EGF. These data suggest that the deletion of the EGFR specifically in ECs attenuates functional hyperemia, likely via depleting PIP2 and subsequently incapacitating Kir2.1 channel functionality in capillary ECs. Thus, our study underscores the role of endothelial EGFR signaling in functional hyperemia of the brain.
摘要：
局部血液灌注的功能性充血-活动依赖性增加-是按需将血液输送到神经元活动增强区域的基础，一个对大脑健康至关重要的过程。重要的是,功能性充血缺陷与多种痴呆危险因素有关,包括衰老，慢性高血压,和脑小血管病（cSVD）。我们先前报道了在遗传cSVD小鼠模型中残缺的功能性充血，这可能是由表皮生长因子受体（EGFR）信号传导受损下游的毛细血管内皮细胞（EC）中磷脂酰肌醇4,5-二磷酸（PIP2）的消耗引起的。这里,使用EC特异性EGFR敲除（KO）小鼠，我们直接检查了内皮EGFR信号在功能性充血中的作用，通过使用激光多普勒血流仪测量响应对侧晶须刺激的脑血流量增加来评估。分子特征显示，EGFR表达在EC-EGFR-KO小鼠新鲜分离的毛细血管中显著降低，如预期。值得注意的是,胡须刺激引起的功能性充血在这些小鼠中明显受损，通过施用PIP2而不是EGFR配体拯救的效应，HB-EGF。这些数据表明，在ECs中特异性的EGFR缺失减弱了功能性充血，可能是通过耗尽PIP2并随后使毛细血管内皮细胞中的Kir2.1通道功能丧失。因此，我们的研究强调了内皮EGFR信号在脑功能性充血中的作用.
