Background and aims: Peripheral arterial disease (PAD) is an important cause of morbidity and mortality with little effective medical treatment currently available. Nitric oxide (NO) is crucially involved in organ perfusion, tissue protection and angiogenesis. Methods: We hypothesized that a novel NO-donor, MPC-1011, might elicit vasodilation, angiogenesis and arteriogenesis and in turn improve limb perfusion, in a hindlimb ischemia model. Hindlimb ischemia was induced by femoral artery ligation in Sprague-Dawley rats, which were randomized to receive either placebo, MPC-1011, cilostazol or both, up to 28 days. Limb blood flow was assessed by laser Doppler imaging. Results: After femoral artery occlusion, limb perfusion in rats receiving MPC-1011 alone or in combination with cilostazol was increased throughout the treatment regimen. Capillary density and the number of arterioles was increased only with MPC-1011. MPC-1011 improved vascular remodeling by increasing luminal diameter in the ischemic limb. Moreover, MPC-1011 stimulated the release of proangiogenic cytokines, including VEGF, SDF1α and increased tissue cGMP levels, reduced platelet activation and aggregation, potentiated proliferation and migration of endothelial cells which was blunted in the presence of soluble guanylyl cyclase inhibitor LY83583. In MPC-1011-treated rats, Lin − / CD31 + /CXCR4 + cells were increased by 92.0% and Lin − /VEGFR2 + /CXCR4 + cells by 76.8% as compared to placebo. Conclusions: Here we show that the NO donor, MPC-1011, is a specific promoter of angiogenesis and arteriogenesis in a hindlimb ischemia model in an NO-cGMP-VEGF-dependent manner. This sets the basis to evaluate and confirm the efficacy of such therapy in a clinical setting in patients with PAD and impaired limb perfusion.

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Positron emission tomography (PET) is a non-invasive nuclear imaging technique that uses radiotracers to track cell activity. The radiopharmaceutical 18F-fluoro-2-deoxyglucose ([ 18 F] FDG) is most commonly used in nuclear medicine for the diagnosis of various diseases, including stroke. A stroke is a serious condition with high mortality and morbidity rates. Rosmarinic acid (RA) is a promising therapeutic agent that exerts neuroprotective effects against various neurological diseases. Therefore, this study aimed to evaluate the applicability of [ 18 F]FDG/ PET for investigating the neuroprotective effects of RA in case of a global stroke model in mice. The [ 18 F]FDG/PET technique facilitates the observation of ischemia and reperfusion injuries in the brain. Moreover, the recovery of glucose metabolism in three specific brain regions, the striatum, superior colliculus, and inferior colliculus, was observed after preconditioning with RA. It was concluded that the [ 18 F]FDG/PET technique may be useful for stroke diagnosis and the assessment of treatment response. In addition, a long-term longitudinal study using biochemical analysis in conjunction with functional imaging may provide further conclusive results regarding the effect of RA on cerebral ischemia.

Introduction: Angiotensin-(1-7) is known by its cardiovascular protective effects by activating MAS receptor. It has been shown that Angiotensin-(1-7) stimulates proliferation of endothelial progenitor cells in vitro, but exerts antiangiogenic effects both in inflammatory and tumor environments in vivo. The role of Angiotensin-(1-7)-MAS axis on ischemic conditions was never reported. Hypothesis: We assessed the hypothesis that MAS receptor signaling plays a role in reparative neovascularization after hindlimb ischemia in mice. METHODS: C57BL/6 wild-type (WT) and MAS receptor knockout (MAS-KO) mice (8-10 weeks) were subjected to unilateral permanent left femoral artery occlusion (FAO). Hindlimb blood flow was measured before and immediately after FAO, and 7 and 14 days after FAO by laser Doppler perfusion imaging (LDPI).To further assess the vascularization in the ischemic limb, 28 days after FAO, we used the technique of microbubles contrast enhanced ultrasound perfusion imaging that enables a more sensitive discrimination of blood flow in deep microvessels. Capillary and arteriole density were evaluated by histological analysis at day 14 after FAO. Results: Vascular density was similar in normoperfused muscles from MAS-KO and WT mice. However, the neovascularization response to hindlimb ischemia was significantly reduced in MAS-KO muscles at capillary (p<0.05; n=4/group) and arteriole (p<0.05; n=4/group) level, which led to lesser perfusion recovery of the ischemic limb of MAS-KO mice as evaluated by LDPI (Day 7: 0.67±0.04 vs 0.85±0.04 ischemic/contralateral ratio, p <0.01; Day 14: 0.62±0.15 vs 0.91±0.03, p<0.001; n=8-12/group). In accordance, we observed that MAS-KO mice require shorter time to peak enhancement of microbubles contrast in ischemic adductor muscles compared with WT mice (p<0.01; n = 5-6/group). Conclusion: In conclusion, our data suggests that post-ischemic hindlimb neovascularization and blood flow recovery are impaired in Angiotensin-(1-7)-MAS receptor knockout mice.