Chapouly Candice, Yao Qinyu, Vandierdonck Soizic, Larrieu-Lahargue Frederic, Mariani John N, Gadeau Alain-Pierre, Renault Marie-Ange
Université de Bordeaux, Adaptation Cardiovasculaire à L'ischémie, U1034, Pessac F-33600, France INSERM, U1034, Adaptation Cardiovasculaire à L'ischémie, 1, Avenue de Magellan, Pessac F-33600, France CHU de Bordeaux, Pharmacie de L'hôpital Haut Lévêque, Pessac F-33600, France.
Université de Bordeaux, Adaptation Cardiovasculaire à L'ischémie, U1034, Pessac F-33600, France INSERM, U1034, Adaptation Cardiovasculaire à L'ischémie, 1, Avenue de Magellan, Pessac F-33600, France.
Cardiovasc Res. 2016 Feb 1;109(2):217-27. doi: 10.1093/cvr/cvv263. Epub 2015 Dec 8.
Microangiopathy, i.e. endothelial dysfunction, has long been suggested to contribute to the development of diabetic neuropathy, although this has never been fully verified. In the present paper, we have identified the role of Hedgehog (Hh) signalling in endoneurial microvessel integrity and evaluated the impact of impaired Hh signalling in endothelial cells (ECs) on nerve function.
By using Desert Hedgehog (Dhh)-deficient mice, we have revealed, that in the absence of Dhh, endoneurial capillaries are abnormally dense and permeable. Furthermore, Smoothened (Smo) conditional KO mice clarified that this increased vessel permeability is specifically due to impaired Hh signalling in ECs and is associated with a down-regulation of Claudin5 (Cldn5). Moreover, impairment of Hh signalling in ECs was sufficient to induce hypoalgesia and neuropathic pain. Finally in Lepr(db/db) type 2 diabetic mice, the loss of Dhh expression observed in the nerve was shown to be associated with increased endoneurial capillary permeability and decreased Cldn5 expression. Conversely, systemic administration of the Smo agonist SAG increased Cldn5 expression, decreased endoneurial capillary permeability, and restored thermal algesia to diabetic mice, demonstrating that loss of Dhh expression is crucial in the development of diabetic neuropathy.
The present work demonstrates the critical role of Dhh in maintaining blood nerve barrier integrity and demonstrates for the first time that endothelial dysfunction is sufficient to induce neuropathy.
长期以来，微血管病变，即内皮功能障碍，一直被认为与糖尿病神经病变的发展有关，尽管这一点从未得到充分证实。在本文中，我们确定了刺猬信号通路（Hh）在神经内膜微血管完整性中的作用，并评估了内皮细胞（ECs）中Hh信号通路受损对神经功能的影响。
通过使用缺乏沙漠刺猬蛋白（Dhh）的小鼠，我们发现，在没有Dhh的情况下，神经内膜毛细血管异常密集且具有通透性。此外，平滑受体（Smo）条件性敲除小鼠表明，这种血管通透性增加具体是由于ECs中Hh信号通路受损，并且与紧密连接蛋白5（Cldn5）的下调有关。此外，ECs中Hh信号通路的受损足以诱导痛觉减退和神经性疼痛。最后，在2型糖尿病瘦素受体（Lepr）db/db小鼠中，观察到神经中Dhh表达的缺失与神经内膜毛细血管通透性增加和Cldn5表达降低有关。相反，全身给予Smo激动剂SAG可增加Cldn5表达，降低神经内膜毛细血管通透性，并恢复糖尿病小鼠的热痛觉，表明Dhh表达缺失在糖尿病神经病变的发展中至关重要。
目前的研究表明Dhh在维持血神经屏障完整性方面起着关键作用，并首次证明内皮功能障碍足以诱发神经病变。
