Src deficiency or blockade of Src activity in mice provides cerebral protection following stroke

Abstract

Vascular endothelial growth factor (VEGF), an angiogenic factor produced in response to ischemic injury, promotes vascular permeability (VP). Evidence is provided that Src kinase regulates VEGF-mediated VP in the brain following stroke and that suppression of Src activity decreases VP thereby minimizing brain injury. Mice lacking pp60c-src are resistant to VEGF-induced VP and show decreased infarct volumes after stroke whereas mice deficient in pp59c-fyn, another Src family member, have normal VEGF-mediated VP and infarct size. Systemic application of a Src-inhibitor given up to six hours following stroke suppressed VP protecting wild-type mice from ischemia-induced brain damage without influencing VEGF expression. This was associated with reduced edema, improved cerebral perfusion and decreased infarct volume 24 hours after injury as measured by magnetic resonance imaging and histological analysis. Thus, Src represents a key intermediate and novel therapeutic target in the pathophysiology of cerebral ischemia where it appears to regulate neuronal damage by influencing VEGF-mediated VP.

Reduced Glioma Infiltration in Src-deficient Mice

“…However, in contrast to the role of VEGF in both angiogenesis and VP, we have focused on the role of VP, specifically using a Src-knockout model to characterize mechanisms of tumor-induced VP in tumor growth and invasion. While we cannot exclude the possibility that other tumor-expressed factors may induce VP, we have shown that although VEGF-induced VP is blocked in Srcdeficient mice, VEGF expression in the brain or fibrinogen expression in the plasma is unchanged in src +/− vs. src −/− mice ( [40,60] and data not shown). We propose that the reduction of tumor-induced VP in the brain vascular bed of src −/− mice mediates a reduction in brain tumor infiltration indirectly by regulating the remodeling of the perivascular ECM.…”

“…Gliomas express a range of growth factors and cytokines, however VEGF is unique among these growth factors in that it induces VP as well as neovascularization [55][56][57][58]. Intra-cranial administration of recombinant VEGF to mice has been shown to increase VP and result in breakdown of the BBB, however the mechanisms regulating this process remain poorly understood [59][60][61]. Therefore, in this study we have examined Src-deficient mice, which we have previously shown to have a 'leakage-resistant' phenotype in response to VEGF.…”

Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor

“…32 Previous studies revealed that inhibition of the Src family kinases Src or Yes through genetic ablation or a pharmacological inhibitor blocked the VP in response to VEGF and protected mice from tissue damage after myocardial infarction or stroke. [12][13][14] To shed light on the mechanism by which Sema3A induces VP, mice were systemically treated with a Src inhibitor SKI-606 and then challenged with subcutaneous injection of Sema3A or VEGF. While pretreatment with SKI-606 abrogated VEGF-induced VP, it had a minimal effect on Sema3A-induced VP ( Figure 5A).…”

“…In fact, we previously showed that genetic or pharmacological inhibition of Src and Yes suppressed VEGF-induced VP, thereby protecting animals from ischemic injury following myocardial infarction and stroke. 12,13 Therefore, the finding that Sema3A suppressed VEGF-mediated VP prompted us to investigate its role as a regulator of VP.…”

lschémie cérébrale

“…Nous avons montré que rendre inactif Src avant une ischémie transitoire empêche à la fois la potentialisation des récepteurs NMDA et la mort neuronale à long terme des neurones CA1 dans l'hippocampe [15]. Enfin, les inhibiteurs de SKF suppriment l'excitotoxicité dépendante de la suractivation des NMDAR in vitro [15,31] mais diminuent également la surface de lésion cérébrale post-ischémique in vivo [32,33]. Ces résultats suggèrent une implication forte des modulations SKF-NMDAR dans le mécanisme physiopathologique de la mort neuronale induite par l'ischémie [29].…”