No abstract

Hyperactivity of the axis ACE/AngII/AT1R of the renin‐angiotensin system is associated with occurrence of acute thrombotic event. Recently a novel concept of a counterrugulatory axis, ACE2/Ang‐(1‐7)/Mas, has emerged. We hypothesized that ACE2 would be protective against thrombosis. Thrombus was induced in the vena cava of SHR and WKY rats by FeCl3 solution. ACE2 and ACE protein expression and activities in the thrombus were determined by Western blot and fluorogenic kinetic assays, respectively. Real time thrombus formation was visualized by intravital microscopy of the vessels of nude mice. Ferric chloride‐induced thrombus weight was 40% higher in the SHR compared to WKY rats. This was associated with a 20% decreased in ACE2 activity in the thrombus of the SHR. In contrast, ACE2 protein expression and ACE activity did not differ between the thrombus of WKY rats and SHR. Inhibition of ACE2 by DX600 increased the thrombus weight by 30%, preferentially in the SHR. Furthermore, treatment with XNT resulted in a 30% attenuation of thrombus formation in both the SHR and WKY. In addition, XNT treatment prolonged the time for complete vessel occlusion and reduced thrombus size when observed under real‐time intravital microscopy. Our data demonstrated that a decrease in ACE2 activity is associated with increased thrombus formation in the SHR. Furthermore, activation of ACE2 attenuates thrombus formation.

Magnetic nanoparticles (MNPs) represent a promising nanomaterial for the targeted therapy and imaging of malignant brain tumors. Conjugation of peptides or antibodies to the surface of MNPs allows direct targeting of the tumor cell surface and potential disruption of active signaling pathways present in tumor cells. Delivery of nanoparticles to malignant brain tumors represents a formidable challenge due to the presence of the blood–brain barrier and infiltrating cancer cells in the normal brain. Newer strategies permit better delivery of MNPs systemically and by direct convection-enhanced delivery to the brain. Completion of a human clinical trial involving direct injection of MNPs into recurrent malignant brain tumors for thermotherapy has established their feasibility, safety and efficacy in patients. Future translational studies are in progress to understand the promising impact of MNPs in the treatment of malignant brain tumors.

Background and Purpose In humans, activin receptor-like kinase 1 (Alk1) deficiency causes arteriovenous malformations (AVMs) in multiple organs, including the brain. Focal Alk1 pan-cellular deletion plus vascular endothelial growth factor (VEGF) stimulation induces brain AVMs (bAVMs) in the adult mouse. We hypothesized that deletion of Alk1 in endothelial cell (EC) alone plus focal VEGF stimulation is sufficient to induce bAVM in the adult mouse. Methods Focal angiogenesis was induced in the brain of eight-week-old Pdgfb-iCreER;Alk12f/2f mice by injection of adeno-associated viral vectors expressing VEGF (AAV-VEGF). Two weeks later, EC-Alk1 deletion was induced by tamoxifen (TM) treatment. Vascular morphology was analyzed, and EC proliferation and Dysplasia Index (number of vessels with diameter >15μm per 200 vessels) were quantified10 days after TM administration. Results Tangles of enlarged vessels resembling AVMs were present in the brain angiogenic region of TM-treated Pdgfb-iCreER;Alk12f/2f mice. Induced bAVMs were marked by increased Dysplasia Index (P<0.001), and EC proliferation clustered within the dysplastic vessels. AVMs were also detected around the ear tag-wound and in other organs. Conclusions Deletion of Alk1 in EC in adult mice leads to an increased local EC proliferation during brain angiogenesis and de novo bAVM.