Vascular endothelial growth factor-A and -C protein up-regulation and early angiogenesis in a rat photothrombotic ring stroke model with spontaneous reperfusion

This study explored the temporal expression pattern of two subtypes of vasc ular endothelial growth factor (VEGF) proteins and three subforms of their receptors as well as endothelial proliferation in adult rats subjected to p hotothrombotic ring stroke with spontaneous reperfusion in the cortical reg ion at risk. The exposed crania of halothane-anesthetized, temperature- and blood gas-controlled male Wistar rats were irradiated with a ring laser be am started simultaneously with systemic injection of the photosensitizer er ythrosin B. Rats were repeatedly injected with 5-bromodeoxyuridine (BrdU) a fter stroke induction. Immunohistochemistry of coronal brain sections showe d that VEGF protein subtype C increased simultaneously with subtype A in th e ring lesion region at 2 h after irradiation. In the cortical region at ri sk (i.e., the penumbra-like zone), increased VEGF-C and VEGF-A immunostaini ng was seen at 24 h with sustained appearance up to 72 h after ischemic ons et. Correspondingly, the VEGF-C-specific receptor flt-4 and the VEGF-A rece ptors flt-1 and flk-1 were up-regulated in a temporal sequence similar to t hat of their agonist proteins in the cortical ring lesion and the region at risk. At 48 h after stroke induction, proliferating BrdU-immunopositive en dothelial cells formed microvessels in the post-ischemic cortical region at risk. These vessels became more pronounced at 72 h and were still visible at 100 days after the stroke. This study suggests that VEGF-C and its recep tor flt-4 may cooperate with VEGF-A and its receptors flt-1 and flk-1 to pr omote early angiogenesis after stroke, which may in turn contribute to spon taneous reperfusion in this focal thromboembolic stroke model.