MicroRNA-155 Exerts Cell-Specific Antiangiogenic but Proarteriogenic Effects During Adaptive Neovascularization

Abstract

During the course of atherosclerotic vascular disease, the adaptive growth of blood vessels is a naturally occurring process that can partly compensate for the decrease in blood flow after the narrowing or occlusion of a major artery. It includes both the sprouting of new endothelial capillaries (angiogenesis) and the enlargement of pre-existing arteriolar and arterial anastomoses to functional collateral arteries (arteriogenesis).1 During angiogenesis, a drop in tissue oxygen tension results in increased expression of hypoxiainducible transcription factors and cytokines, stimulating endothelial proliferation and sprouting in the ischemic tissue, improving distribution and use of the remaining blood flow. On the other hand, arteriogenesis is characterized by a well-orchestrated inflammatory response that is not restricted to the endothelial cell (EC) layer but facilitated by the perivascular infiltration of bone marrow-derived cell populations, mediating the proliferation of both endothelial and vascular smooth muscle cells. During the past decade, monocytes and macrophages were especially demonstrated to exert an important stimulatory function in the regulation of collateral artery growth.2 Although our knowledge about these contributing cell populations in the different forms of vascular growth steadily increases, our understanding of the basic regulatory principles controlling these processes is still limited. Other than canonical mediators of blood vessel growth, such as growth factors and their receptors, an additional functional group of regulators has recently emerged: microRNAs (miRNAs). These short (17-24 nucleotides), single-stranded regulatory RNA sequences are transcribed as precursor hairpin structures from intergenic or intronic regions of the genome that undergo several nuclear and cytoplasmatic processing steps to the mature miRNA.3 Together with Argonaute proteins, they form the RNA-induced silencing complex and recognize specific sequences mostly located in the 3′ untranslated region of their target mRNA, resulting either in inhibition of translation or degradation of Background-Adaptive neovascularization after arterial occlusion is an important compensatory mechanism in cardiovascular disease and includes both the remodeling of pre-existing vessels to collateral arteries (arteriogenesis) and angiogenic capillary growth. We now aimed to identify regulatory microRNAs involved in the modulation of neovascularization after femoral artery occlusion in mice. Methods and Results-Using microRNA-transcriptome analysis, we identified miR-155 as a downregulated microRNA during hindlimb ischemia. Correspondingly, inhibition of miR-155 in endothelial cells had a stimulatory effect on proliferation and angiogenic tube formation via derepression of its direct target gene angiotensin II type 1 receptor. Surprisingly, miR-155-deficient mice showed an unexpected phenotype in vivo, with a strong reduction of blood flow recovery after femoral artery ligation (arteriogenesis) dependent on the attenuation of leuko...

Exposure of Endothelium to Biomimetic Flow Waveforms Yields Identification of miR-199a-5p as a Potent Regulator of Arteriogenesis

“…Despite a number of previous reports indicating miRNA regulation of perfusion recovery in hindlimb ischemia models,19, 20, 21, 22, 23, 24, 25, 26, 27, 68 only a few of these miRNAs (e.g., miR-155, miR-17∼92a, miR-93, miR-487b, and miR-352) have been suggested to have a role in arteriogenesis per se. Inhibition of miR-155 attenuates blood flow recovery and leukocyte recruitment, despite promoting angiogenesis in the ischemic tissue of FAL-treated mice, thereby indirectly implying a role for miR-155 in arteriogenesis.…”

“…Additionally, miRNAs are attractive as potential therapeutic targets as they are short, highly conserved, and can negatively regulate gene expression of multiple mRNA targets 18 . Several miRNAs have been implicated as regulators of vascular growth, primarily angiogenesis in ischemic tissue, in response to arterial occlusion 19, 20, 21, 22, 23, 24, 25, 26, 27. However, the explicit role of mechanosensitive miRNAs in collateral arteriogenesis is poorly understood.…”

Predictive Effects of Circulating miR-221, miR-130a and miR-155 for Coronary Heart Disease: A Multi-Ethnic Study in China

“…Interestingly, treatment with atorvastatin increased EPC numbers and decreased miR-221/222 levels in patients with CHD [55]. As for miR-155, it has been demonstrated thatmiR-155 exerts an antiangiogenic but proarteriogenic function in the regulation of neovascularization via the suppression of divergent cell-specific target genes in mice [56]. In fact, a previous study has concluded that circulating miR-155 is lower in CHD patients, and inversely associated with the extent of coronary stenosis as indicated by the Gensini Scores [57].…”

Polycyclic Aromatic Hydrocarbons from Particulate Matter 2.5 (PM2.5) in Polluted Air Changes miRNA Profile Related to Cardiovascular Disease

“…Angiotensin II-induced endothelial inflammation and migration are regulated by microRNA-155 [18]. During adaptive neovascularization, miRNA-155 plays an important role in cell-specific antiangiogenesis [19]. Atherosclerosis is promoted by miRNA-155 through the repression of Bcl6 [20].…”