The NO-donor MPC-1011 stimulates angiogenesis and arteriogenesis and improves hindlimb ischemia via a cGMP-dependent pathway involving VEGF and SDF-1α

Abstract

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.

The Role of the VEGF Family in Atherosclerosis Development and Its Potential as Treatment Targets

“…Similarly, plaque stabilisation was achieved with F8-antibody/VEGF-C conjugates applied on ApoE −/− mice atherosclerosis model [78]. Furthermore, promising NO-releasing drug MPC-1011 used in the rat hindlimb ischemia model of PAD (peripheral arterial dis-ease) was shown to act in the NO/cGMP/VEGF-dependent way [79]. PAD is caused mainly by atherosclerosis and is characterised by impaired blood flow to the lower extremities, severe exercise intolerance and claudication pain [80].…”

“…PAD is caused mainly by atherosclerosis and is characterised by impaired blood flow to the lower extremities, severe exercise intolerance and claudication pain [80]. MPC-1011 treatment improved vascular remodelling and stimulated the release of VEGF, SDF1 (Stromal Cell-Derived Factor 1) and increased tissue cGMP levels, potentiated proliferation and migration of ECs, reduced platelet activation and aggregation [79].…”

Effect of oral intake of royal jelly on endothelium function in hemodialysis patients: study protocol for multicenter, double-blind, randomized control trial

“…FMD is widely used to measure endothelial function under various pathological conditions [ 36 – 38 ]. In addition, to clarify the repair of vascular endothelium, we will also measure serum VEGF levels because VEGF is a major regulator of endothelial cell growth and migration [ 39 ]. The degree of vascular calcification will be assessed using ACI.…”

Therapeutic Biomaterial Approaches to Alleviate Chronic Limb Threatening Ischemia

“…[ 113 ] Additionally, NO has shown the ability to favor the expression of pro‐angiogenic cytokines and growth factors in MSCs. [ 114 ] Despite its therapeutic potential, its utilization is limited due to short half‐life and the lack of effective delivery strategies that limit its angiogenic effect in vivo. Consequently, systems that allow a sustained and controllable deliverable are needed for its application.…”