Micromanaging restenosis by therapeutic inhibition of miR-92a.

The adverse consequences of procedure-associated endovascular injury may limit the long-term benefits of coronary interventions like angioplasty and stent insertion. Damage to the artery’s endothelium and impaired re-endothelialization, also caused by the use of nonselective anti-proliferative drugs, may promote the development of restenosis—a pathological condition characterized by smooth muscle cell (SMC) hyperplasia, vessel thickening and lumen narrowing, and impaired blood flow—in a significant proportion of the patients. Reducing the occurrence of restenosis after coronary interventions thus remains an important medical need. In this issue of Cardiovascular Research, Daniel et al. 2 report that both genetic and molecular (therapeutic) approaches to inhibit microRNA (miRNA)-92a facilitate arterial reendothelialization and prevent restenosis in a mouse model of femoral artery injury. miRNAs are a class of small non-coding RNAs that fine-tune gene expression at the post-transcriptional level. Several miRNAs, including miR-126, miR-132, miR-222, and miR-92a, have been implicated in the regulation of endothelial cell (EC) biology. miR-92a is a member of the miR-17-92 cluster, which encodes six distinct miRNAs broadly involved in physiological and pathological processes such as cell proliferation, development, immunity, and tumorigenesis. While being deregulated in several leukaemias and solid tumours, miR-92a also functions as a negative regulator of EC proliferation, angiogenesis, and vascular repair. Therapeutic modulation of miR-92a activity in ECs may, therefore, rescue the damaged endothelium after coronary interventions. 8 Daniel et al. employed a mouse model of wire-induced injury of the femoral artery to analyse the temporal and cellular expression of miR-92a after vascular damage. They found that miR-92a levels increased post-injury and peaked at Day 10, a time-point when SMC hyperplasia was already evident in the injured artery. The analysis of cultured ECs and SMCs, as well as intact or endothelium-denudated arteries, suggested thatECsandnotSMCs were themain sourceofmiR-92a in the injured arteries. Moreover, transfection of miR-92a inhibited vascular endothelial growth factor-A (VEGFA)-induced EC proliferation and migration, but did not affect platelet-derived growth factor-BB (PDGFB)-induced SMC proliferation or migration, indicating that the functions of miR-92a are largely EC-autonomous. The authors then used two loss-of-function strategies to attenuate miR-92a activity in the damaged arteries. Both the systemic delivery of locked nucleic acid (LNA)-modified anti-miR-92a oligonucleotides and the conditional knockout of miR-92a in TIE2+ ECs stimulated re-endothelialization and decreased SMC hyperplasia and inflammatory–macrophage infiltration in the femoral artery after wire-induced injury (Figure 1). These data suggest that suppression of endothelial miR-92a activity promotes arterial re-endothelialization and limits SMC hyperplasia, at least in part, through direct pro-proliferative effects on ECs. Consistent with these findings, previous studies showed that inhibition of miR-92a enhances VEGFA-induced EC proliferation by activating mitogenic ERK and JNK signalling. Besides direct pro-proliferative effects on ECs, inhibition of miR-92a may attenuate experimental restenosis through additional mechanisms. Among the validated targets of miR-92a are the deacetylase sirtuin-1 (Sirt1) and integrin-a5 (Itga5). SIRT1 is highlyexpressed in the angiogenic vasculature and promotes sprouting angiogenesis, whereas ITGA5 enables migration, pro-angiogenic signalling, and angiogenesis of ECs by modulating their interactions with the extra-cellular matrix. Daniel et al. observed increased expression of both SIRT1 and ITGA5 in the arterial ECs of anti-miR-92a–treated mice 2 weeks post-injury, suggesting that therapeutic inhibition of miR-92a stimulates re-endothelialization, at least in part, by de-repressing both proangiogenic factors. miR-92a also targets the transcription factors Krüppel-like factor-2 (KLF2) and 4, which confer anti-inflammatory and atheroprotective properties to the endothelium. De-repressed KLF2 and 4 may operate to down-regulate the expression of leucocyte adhesion molecules on ECs, hence limiting inflammatory cell infiltration, and to enhance endothelial nitric oxide (NO) synthetase (NOS3/ eNOS) activity, which inhibits SMC proliferation through NO production. Thus, therapeutic inhibition of miR-92a may initiate an anti-atherosclerotic programme in ECs that limits inflammatory cell infiltration and SMC proliferation in the healing arteries. –8 Daniel et al. andprevious studies –8 employedanti-miR-92a oligonucleotides delivered systemically in animal models of vascular injury.