Thrombolysis exacerbates cerebrovascular injury after ischemic stroke via a VEGF-B dependent effect on adipose lipolysis.

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.
Competing Interests: Declaration of interest I.N., E.J.S, D.A.L. and U.E. hold patents on the method of reducing the effect of stroke using a VEGF-B inhibitor, and of treating stroke by inhibition of VEGF-B signaling in combination with a thrombolytic agent. I.N., L.F., C.M., M.Z., L.M. and U.E. are shareholders in a company within the diabetes field. P.D.S. is an employee of, and shareholder in CSL Limited, a biopharmaceutical company. U.E. is a member of a scientific advisory board of a hedge fund in the biotech sector. No other authors have declared competing interest.