Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, is a widely used anticonvulsant drug that is currently undergoing clinical evaluation for anticancer therapy due to its anti-angiogenic potential. Endothelial cells (ECs) can transition into mesenchymal cells and this form of EC plasticity is called endothelial-to-mesenchymal transition (EndMT), which is widely implicated in several pathologies including cancer and organ fibrosis. However, the effect of VPA on EC plasticity and EndMT remains completely unknown. We report herein that VPA-treatment significantly inhibits tube formation, migration, nitric oxide production, proliferation and migration in ECs. A microscopic evaluation revealed, and qPCR, immunofluorescence and immunoblotting data confirmed EndMT-like phenotypic switching as well as an increased expression of pro-fibrotic genes in VPA-treated ECs. Furthermore, our data confirmed important and regulatory role played by TGFβ-signaling in VPA-induced EndMT. Our qPCR array data performed for 84 endothelial genes further supported our findings and demonstrated 28 significantly and differentially regulated genes mainly implicated in angiogenesis, endothelial function, EndMT and fibrosis. We, for the first time report that VPA-treatment associated EndMT contributes to the VPA-associated loss of endothelial function. Our data also suggest that VPA based therapeutics may exacerbate endothelial dysfunction and EndMT-related phenotype in patients undergoing anticonvulsant or anticancer therapy, warranting further investigation.

BackgroundCurrent limitations to the experimentation on patients with peripheral arterial disease push the development of different preclinical strategies. We investigated both duration of ischemia and blood flow recovery in mouse models of partial femoral artery ligation.MethodsMale BALB/c mice were used. The ligation over needle method involved placing a suture needle over the femoral artery, ligating over it and then removing the needle. The transfixation method involved transfixing the approximate center of the femoral artery and then tying the suture. Laser Doppler Perfusion Imaging was used to assess perfusion every 3rd day until 42 days after the procedure.ResultsLigation over needle method: Immediately post procedure, mean perfusion was -71.87% ± 4.43. Then mean difference in perfusion remained below the base line reading on days 3, 6, 9, and 12. From day 15 on wards mean perfusion progressively improved remaining near base line. Transfixation Method: Immediately post procedure mean perfusion was -70.82% ± 4.73. Mean perfusion improved following the procedure on days 3 and 6; a plateau followed this on days 9, 12 and 15. From day 15 onwards perfusion progressively improved remaining well below base line until crossing it on day 36.ConclusionThe currently described models do not pose major improvements over previously described methods.

Brachial artery aneurysms and arteriovenous malformations (AVM) are limb-threatening vascular anomalies. This patient presented with a bilobed brachial artery aneurysm in the antecubital fossa proximally to an AVM arising from the dorsal interosseous and ulnar arteries that had been treated with endovascular embolization, leaving the hand solely supplied by the radial artery. The aneurysm continued to increase in size and imaging revealed concomitant thrombus. A femoral vein interposition graft was used to repair the aneurysm, and postoperatively, the patient retained full left arm function.