As a neuropeptide Apelin also

As a neuropeptide, Apelin also has a critical role in cardiovascular diseases. Systemic administration of Apelin exert vasodilatory and antihypertensive effects [33]. Meanwhile, the apelin-APJ signal transduction pathway is related to age-associated cardiovascular diseases [34]. It has been known that apelin induces endothelial cell proliferation. Consistent with our findings, Eyries et al. have found that hypoxia can induce apelin expression to regulate endothelial cell proliferation and regenerative angiogenesis [35]. Zhang J. et al. have also demonstrated that elevation of Apelin or APLNR expression increases hypoxia-induced cellular growth of the EPCs, while silence of Apelin or APLNR by siRNA inhibits the hypoxia-induced EPC proliferation [36], [37]. However, our data further confirmed the role of Apelin in endothelial migration and angiogenesis. Meanwhile, the PI3K and MAPK pathways were involved in Apelin-induced EPC proliferation [36], [37]. It is meaningful to elucidate the effect of miR-503 on the MAPK and PI3K pathways in our future studies. On the other hand, the mechanisms underlying Apelin/APLNR signaling pathway involved in hypoxia-induced EPC growth, migration and angiogenesis requires further investigation. For the relationship between miR-503 and Apelin, Zhou et al. have also demonstrated that miR-503 promotes cardiac fibrosis via targeting Apelin [38], which is consistent with our results in endothelial cells. Actually, the role of miR-503 and Apelin in endothelial cell proliferation and angiogenesis is much disputed. Kim et al. have defined a novel relationship between the APLN and FGF signaling pathways in the pulmonary vasculature that is mediated by two APLN-regulated miRNAs: miR-424 and miR-503. In contrast, our findings have revealed that miR-503 was downregulated by hypoxia. Functionally, Kim et al. have demonstrated that overexpression of miR-503 in pulmonary artery endothelial 82 7 (PAECs) promoted cellular quiescence and inhibited the capacity of PAEC conditioned media to induce proliferation of pulmonary artery smooth muscle cells [39]. Thus, miR-503 exerts an anti-proliferative effect and inhibits the proliferation of PAECs [40]. Consistently, our results have also indicated that miR-503 is an anti-proliferative and an anti-angiogenetic miRNA in endothelial cells. In hepatocarcinoma, Zhou et al. have also found that miR-503 expression is down-regulated by hypoxia through HIF1α and miR-503 can simultaneously down-regulate FGF2 and VEGFA to suppress tumor angiogenesis and growth. In Diabetes mellitus, blocking miR-503 activity can improve the functional capacities of ECs cultured under high D-glucose/low growth factors[41]. Meanwhile, miR-503 induces apoptosis and cell-cycle arrest and inhibits cell proliferation, angiogenesis, and contractility of human ovarian endometriotic stromal cells [42]. Nie et al. have identified 57 miRNAs that are upregulated in MSCs with exposure to hypoxia for 6 h including miR-503 [18], which is inconsistent to our findings. We suppose that the regulation of miR-503 is cell-type specific. In addition, previous studies have demonstrated that elevation of miR-503 expression leads to the suppression of tumor angiogenesis through regulation of FGF2 and VEGFA [43], while miR-503 expression reduction elevates the production of VEGF of lung fibroblast in patients with chronic obstructive pulmonary disease [44]. In the present study, our unpublished data showed that ectopic expression of miR-503 could not modulate the VEGF expression in hypoxia-treated EPCs. These findings suggest that the targets of miR-503 may be cell-type dependent. On the other hand, despite of cell proliferation, migration and angiogenesis, previous literatures have reported that hypoxia suppresses the senescence of EPCs and stimulates endothelial cells to secret inflammatory factors [45]. The putative role of miR-503/Apelin axis in regulating EPC senescence and inflammation remain to be well elucidated in our future studies.