PDF(Pubmed)
Abstract：
Vascular smooth muscle cells (VSMCs) envelop vertebrate brain arteries and play a crucial role in regulating cerebral blood flow and neurovascular coupling. The dedifferentiation of VSMCs is implicated in cerebrovascular disease and neurodegeneration. Despite its importance, the process of VSMC differentiation on brain arteries during development remains inadequately characterized. Understanding this process could aid in reprogramming and regenerating dedifferentiated VSMCs in cerebrovascular diseases. In this study, we investigated VSMC differentiation on zebrafish circle of Willis (CoW), comprising major arteries that supply blood to the vertebrate brain. We observed that arterial specification of CoW endothelial cells (ECs) occurs after their migration from cranial venous plexus to form CoW arteries. Subsequently, acta2+ VSMCs differentiate from pdgfrb+ mural cell progenitors after they were recruited to CoW arteries. The progression of VSMC differentiation exhibits a spatiotemporal pattern, advancing from anterior to posterior CoW arteries. Analysis of blood flow suggests that earlier VSMC differentiation in anterior CoW arteries correlates with higher red blood cell velocity and wall shear stress. Furthermore, pulsatile flow induces differentiation of human brain PDGFRB+ mural cells into VSMCs, and blood flow is required for VSMC differentiation on zebrafish CoW arteries. Consistently, flow-responsive transcription factor klf2a is activated in ECs of CoW arteries prior to VSMC differentiation, and klf2a knockdown delays VSMC differentiation on anterior CoW arteries. In summary, our findings highlight blood flow activation of endothelial klf2a as a mechanism regulating initial VSMC differentiation on vertebrate brain arteries.
摘要：
血管平滑肌细胞（VSMC）包裹脊椎动物脑动脉，在调节脑血流量和神经血管耦合中起着至关重要的作用。VSMC的去分化与脑血管疾病和神经变性有关。尽管它很重要,在发育过程中脑动脉上的VSMC分化过程仍未得到充分表征。了解此过程可以帮助在脑血管疾病中重新编程和再生去分化的VSMC。在这项研究中,我们研究了威利斯斑马鱼圈上的VSMC分化，包括向脊椎动物大脑供血的主要动脉。我们观察到CoW内皮细胞（ECs）从颅静脉丛迁移形成CoW动脉后发生动脉特化。随后，acta2+VSMC在募集到CoW动脉后与pdgfrb+壁细胞祖细胞区分开。VSMC分化的进展表现出一种时空模式，从前向后推进CoW动脉。血流分析表明，CoW前动脉中早期的VSMC分化与较高的红细胞速度和壁切应力相关。此外，脉冲流诱导人脑PDGFRB+壁细胞分化为VSMC，斑马鱼CoW动脉VSMC分化需要血流量。始终如一，血流响应性转录因子klf2a在VSMC分化之前在CoW动脉的ECs中被激活，和klf2a敲低延迟了CoW前动脉的VSMC分化。总之,我们的发现强调了内皮klf2a的血流激活是调节脊椎动物脑动脉初始VSMC分化的机制。
