MicroRNA Manipulation to Boost Endothelial Regeneration: Are We Ready for the Next Steps?

Cardiovascular complications are the main cause of death in subjects with diabetes and represent an ever-growing burden on health care systems throughout the world, and especially in Western society (1). People with diabetes show a high incidence to develop atherosclerosis and major cardiovascular accidents as a consequence of the complex interactions among insulin resistance, hyperglycemia, and associated metabolic abnormalities (2). However, despite the considerable efforts that have been devoted to the understanding of the processes by which chronic hyperglycemia promotes the development and the progression of atherosclerosis, these processes have not been fully elucidated yet and novel ways to prevent development or treat macrovascular and microvascular diseases are of particular interest. Endothelial dysfunction is considered a crucial event in the pathogenesis of vascular disease in diabetes, and an early detection of cellular and molecular mechanisms related to the imbalance between damage of endothelial cells and their impaired repair may give rise to new and efficient preventive and therapeutic strategies (3).

Loss of endothelial cells due to increased cell death and impaired regeneration is a major contributor to the extent of endothelial dysfunction (4). Endothelium itself has a relatively weak capacity to self-repair due to low proliferative capacity. However, recently it has become evident that cells, recruited from the bone marrow and from other tissues, circulate in the peripheral blood and have the ability to promote reendothelialization after injury (5). In addition to classic endothelial progenitor cells, other hematopoietic lineage cells, such as M2-like macrophages or T lymphocytes, may support endothelium regeneration (6).

Several studies demonstrated that in vivo reendothelialization capacity is severely impaired in patients with diabetes (5,7,8). In this issue of Diabetes, Kuschnerus et al. (9) confirm the relevant role of M2-like macrophages in endothelium regeneration, showing in vivo that the endothelial regeneration potential of M2-like macrophages derived from patients with diabetes is severely impaired as a result of increased expression of microRNA (miR)-483-3p. Notably, the authors show a marked increased expression of miR-483-3p in the diabetic human vascular wall as well as in the carotid artery of diabetic mice (9). A therapeutic approach based on miR-483-3p inhibition through an LNA-based anti-miR enhances reendothelialization in vivo, suggesting that miR-483-3p inhibitors show promising therapeutic potential for the treatment of cardiovascular disease in patients with diabetes. In vitro modulation of miR-483-3p levels did not directly influence proliferation but did increase apoptosis in both endothelial and macrophage cells. Therefore, the mechanisms underlying the therapeutic benefit of LNA anti–miR-483-3p very likely involve a direct proregenerative effect on local endothelial cells adjacent to the injury and the ability to modulate M2-like macrophage signals to promote the regeneration of injured tissue (Fig. 1). miR-483-3p influences many biological processes, and it is deregulated in different types of cancer (10). The association of glucose metabolism to the regulation of miR-483-3p is supported by the fact that miR-483-3p maps at the INS-IGF2 locus, which is involved in the insulin pathway (11). Additionally, it was observed that miR-483-3p is abnormally expressed in diabetic cardiomyopathy and promotes apoptosis by targeting the IGF1 gene (12). miR-483-3p has been also reported to control angiogenesis in vitro by targeting the serum response factor, representing a potential therapeutic target for improving neovascularization in ischemic heart disease (13). The apoptotic effect of miR-483-3p is consistent with previous findings; however, the mechanisms by which miR-483-3p may be induced remained unclear because in the current study miR-483-3p expression was not affected by hyperglycemia and showed a strikingly different expression pattern when comparing endothelial and macrophage cells. This finding, added to the difficulties in defining the relevant target gene that is affected by miR-483-3p in the context of endothelium regeneration, points to cell-specific regulation pathways. Vascular endothelial zinc finger 1 (VEZF1) is a potential candidate to explain the link between miR-483-3p and reduced endothelial regeneration. The discovery of VEZF1 as an endothelial transcription factor and its role in angiogenesis is relatively new. Genetic knockout studies revealed the role of VEZF1 in vascularization; however, the mechanism of its regulation is not fully understood (14–17). Therefore, further studies are necessary to define the role of miR-483-3p and VEZF1 pathway in diabetes-induced vascular complications.

Despite the limited mechanistic insights into the detailed functions of the miR-483-3p, the study by Kuschnerus et al. (9) provides many interesting aspects and highlights the central role of miR-483-3p in endothelium regeneration. Rapid endothelialization is essential for the development of vascular grafts (18). A rapidly growing approach is the insertion of miRNAs or antagomirs as drugs eluted from stents positioned in patients after balloon dilation of arteries (19). This is a potential therapeutic scenario that might change our ability to interfere with rapidly growing processes, such as restenosis, in vivo through the contextual effect on several genes obtained by few miRNAs or antagomirs in a very restricted area and manner. miR-483-3p is the new kid on the block in this promising area of molecular medicine.