Guldbrandsen Halvor Osterby, Staehr Christian, Iversen Nina Kerting, Postnov Dmitry D, Matchkov Vladimir V
Department of Biomedicine, MEMBRANES, Health (H.O.G., C.S., V.V.M.), Aarhus University, Denmark.
Center of Functionally Integrative Neuroscience, Institute for Clinical Medicine (N.K.I.), Aarhus University, Denmark.
Stroke. 2021 Jun;52(6):e250-e258. doi: 10.1161/STROKEAHA.120.032737. Epub 2021 May 5.
Despite successful recanalization, a significant number of patients with ischemic stroke experience impaired local brain tissue reperfusion with adverse clinical outcome. The cause and mechanism of this multifactorial complication are yet to be understood. At the current moment, major attention is given to dysfunction in blood-brain barrier and capillary blood flow but contribution of exaggerated constriction of cerebral arterioles has also been suggested. In the brain, arterioles significantly contribute to vascular resistance and thus control of perfusion. Accordingly, pathological changes in arteriolar wall function can, therefore, limit sufficient reperfusion in ischemic stroke, but this has not yet received sufficient attention. Although an increased vascular tone after reperfusion has been demonstrated in several studies, the mechanism behind it remains to be characterized. Importantly, the majority of conventional mechanisms controlling vascular contraction failed to explain elevated cerebrovascular tone after reperfusion. We propose here that the Na,K-ATPase-dependent Src kinase activation are the key mechanisms responsible for elevation of cerebrovascular tone after reperfusion. The Na,K-ATPase, which is essential to control intracellular ion homeostasis, also executes numerous signaling functions. Under hypoxic conditions, the Na,K-ATPase is endocytosed from the membrane of vascular smooth muscle cells. This initiates the Src kinase signaling pathway that sensitizes the contractile machinery to intracellular Ca resulting in hypercontractility of vascular smooth muscle cells and, thus, elevated cerebrovascular tone that can contribute to impaired reperfusion after stroke. This mechanism integrates with cerebral edema that was suggested to underlie impaired reperfusion and is further supported by several studies, which are discussed in this article. However, final demonstration of the molecular mechanism behind Src kinase-associated arteriolar hypercontractility in stroke remains to be done.
尽管实现了成功再通，但仍有相当数量的缺血性中风患者存在局部脑组织再灌注受损，并伴有不良临床后果。这种多因素并发症的原因和机制尚不清楚。目前，主要关注血脑屏障功能障碍和毛细血管血流，但也有人提出脑小动脉过度收缩也有影响。在大脑中，小动脉对血管阻力有显著影响，从而控制灌注。因此，小动脉壁功能的病理变化会限制缺血性中风时的充分再灌注，但这一点尚未得到足够重视。尽管多项研究已证实再灌注后血管张力增加，但其背后的机制仍有待明确。重要的是，大多数控制血管收缩的传统机制无法解释再灌注后脑血管张力升高的现象。我们在此提出，钠钾ATP酶依赖性Src激酶激活是再灌注后脑血管张力升高的关键机制。钠钾ATP酶对控制细胞内离子稳态至关重要，还执行多种信号功能。在缺氧条件下，钠钾ATP酶从血管平滑肌细胞膜内吞。这启动了Src激酶信号通路，使收缩机制对细胞内钙敏感，导致血管平滑肌细胞过度收缩，进而使脑血管张力升高，这可能导致中风后再灌注受损。这种机制与被认为是再灌注受损基础的脑水肿相关，本文讨论的多项研究进一步支持了这一点。然而中风中Src激酶相关小动脉过度收缩背后分子机制的最终证明仍有待完成。
