Nilsson Ingrid, Su Enming J, Fredriksson Linda, Sahlgren Benjamin Heller, Bagoly Zsuzsa, Moessinger Christine, Stefanitsch Christina, Ning Frank Chenfei, Zeitelhofer Manuel, Muhl Lars, Lawrence Anna-Lisa E, Scotney Pierre D, Lu Li, Samén Erik, Ho Heidi, Keep Richard F, Medcalf Robert L, Lawrence Daniel A, Eriksson Ulf
Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet, Stockholm, Sweden.
These authors contributed equally.
bioRxiv. 2024 Oct 12:2024.10.11.617532. doi: 10.1101/2024.10.11.617532.
Cerebrovascular injuries leading to edema and hemorrhage after ischemic stroke are common. The mechanisms underlying these events and how they are connected to known risk factors for poor outcome, like obesity and diabetes, is relatively unknown. Herein we demonstrate that increased adipose tissue lipolysis is a dominating risk factor for the development of a compromised cerebrovasculature in ischemic stroke. Reducing adipose lipolysis by VEGF-B antagonism improved vascular integrity by reducing ectopic cerebrovascular lipid deposition. Thrombolytic therapy in ischemic stroke using tissue plasminogen activator (tPA) leads to increased risk of hemorrhagic complications, substantially limiting the use of thrombolytic therapy. We provide evidence that thrombolysis with tPA promotes adipose tissue lipolysis, leading to a rise in plasma fatty acids and lipid accumulation in the ischemic cerebrovasculature after stroke. VEGF-B blockade improved the efficacy and safety of thrombolysis suggesting the potential use of anti-VEGF-B therapy to extend the therapeutic window for stroke management.
缺血性中风后导致水肿和出血的脑血管损伤很常见。这些事件背后的机制以及它们如何与肥胖和糖尿病等已知的不良预后风险因素相关联，目前相对尚不明确。在此我们证明，脂肪组织脂解增加是缺血性中风中脑血管受损发展的主要危险因素。通过拮抗血管内皮生长因子B（VEGF - B）减少脂肪脂解，可通过减少异位脑血管脂质沉积来改善血管完整性。使用组织型纤溶酶原激活剂（tPA）进行缺血性中风溶栓治疗会增加出血并发症的风险，从而极大地限制了溶栓治疗的应用。我们提供的证据表明，tPA溶栓会促进脂肪组织脂解，导致中风后缺血性脑血管中血浆脂肪酸升高和脂质积累。VEGF - B阻断改善了溶栓的疗效和安全性，这表明抗VEGF - B疗法有可能用于延长中风治疗的时间窗。
