Therapeutic manipulation of angiogenesis with miR-27b

Abstract

BackgroundMultiple studies demonstrated pro-angiogenic effects of microRNA (miR)-27b. Its targets include Notch ligand Dll4, Sprouty (Spry)-2, PPARγ and Semaphorin (SEMA) 6A. miR-27 effects in the heart are context-dependent: although it is necessary for ventricular maturation, targeted overexpression in cardiomyocytes causes hypertrophy and dysfunction during development. Despite significant recent advances, therapeutic potential of miR-27b in cardiovascular disease and its effects in adult heart remain unexplored. Here, we assessed the therapeutic potential of miR-27b mimics and inhibitors in rodent models of ischemic disease and cancer.MethodsWe have used a number of models to demonstrate the effects of miR-27b mimicry and inhibition in vivo, including subcutaneous Matrigel plug assay, mouse models of hind limb ischemia and myocardial infarction and subcutaneous Lewis Lung carcinoma.ResultsUsing mouse model of myocardial infarction due to the coronary artery ligation, we showed that miR-27b mimic had overall beneficial effects, including increased vascularization, decreased fibrosis and increased ejection fraction. In mouse model of critical limb ischemia, miR-27b mimic also improved tissue re-vascularization and perfusion. In both models, miR-27b mimic clearly decreased macrophage recruitment to the site of hypoxic injury. In contrast, miR-27b increased the recruitment of bone marrow derived cells to the neovasculature, as was shown using mice reconstituted with fluorescence-tagged bone marrow. These effects were due, at least in part, to the decreased expression of Dll4, PPARγ and IL10. In contrast, blocking miR-27b significantly decreased vascularization and reduced growth of subcutaneous tumors and decreased BMDCs recruitment to the tumor vasculature.ConclusionsOur study demonstrates the utility of manipulating miR-27b levels in the treatment of cardiovascular disease and cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13221-015-0031-1) contains supplementary material, which is available to authorized users.

The regulatory role of microRNAs in angiogenesis‐related diseases

“…Recently, increasing studies demonstrated that the roles of miR‐27b are completely different in different type cancers and vascular diseases 144, 145, 146, 147. A study showed that miR‐27b improves angiogenesis in impaired bone marrow‐derived angiogenic cells (BMAC) in vitro and in vivo in type 2 diabetic mice via directly inhibiting the expression of thrombospondin‐1 (TSP‐1), p66 (shc) and Semaphorin6A (Sema6A), thereby improving the topical cell therapy of diabetic BCACs on wound healing and increasing the wound perfusion and capillary formation 144.…”

“…A study showed that miR‐27b improves angiogenesis in impaired bone marrow‐derived angiogenic cells (BMAC) in vitro and in vivo in type 2 diabetic mice via directly inhibiting the expression of thrombospondin‐1 (TSP‐1), p66 (shc) and Semaphorin6A (Sema6A), thereby improving the topical cell therapy of diabetic BCACs on wound healing and increasing the wound perfusion and capillary formation 144. In addition, miR‐27b mimic has overall beneficial effects, including reducing fibrosis and macrophage recruitment to the site of hypoxic injury, enhancing vascularization, ejection fraction and the recruitment of bone marrow‐derived cells (BMDCs) to the neovasculature 146. In contrast, repressing miR‐27b observably restrains vascularization, the growth of subcutaneous tumours and BMDC recruitment to the tumour vasculature.…”

“…Moreover, miR‐27b improves EC proliferation and migration by directly repressing Sprouty2 (Spry2), Sema6A, and Semaphorin 6D (Sema6D) in response to VEGF, thereby promoting angiogenesis 147. Furthermore, miR‐27b enhances angiogenesis and ejection fraction in a mouse model of MI and also increases tissue revascularization and perfusion in a mouse model of critical limb ischaemia via repressing the expression of delta‐like ligand 4 (Dll4), peroxisome proliferator‐activated receptor γ (PPARγ) and IL‐10 146. Coincidently, miR‐27b inhibitor inhibits tumour growth and angiogenesis in lung carcinoma 146.…”

Increased Wnt5a in squamous cell lung carcinoma inhibits endothelial cell motility

“…In the literature PPARgamma has been described to have a highly conserved binding site in its 3′UTR that is a direct target of miR-27b [48]. Binding of miR-27b to its target sequence can suppress PPARgamma expression [49] and augment VEGF-A induced angiogenesis [50]. Importantly, both miR-27b as well as another miRNA, miR-200b can inhibit blood vessel branching during angiogenesis [51, 52].…”

“…Interestingly, Wnt5a can up-regulate miR-27b which miRNA has been reported to bind to the highly conserved binding site in the 3′UTR of PPARgamma [48] and suppress its expression [49]. Consequently, up-regulation of VEGF-A [50] can use this particular route (Fig. 5).…”