Role of MicroRNA-150 and Glycoprotein Nonmetastatic Melanoma Protein B in Angiogenesis during Hyperoxia-Induced Neonatal Lung Injury

Abstract

Glycoprotein nonmetastatic melanoma protein B (GPNMB), a transmembrane protein, has been reported to have an important role in tissue repair and angiogenesis. Recently, we have demonstrated that hyperoxia exposure down-regulates microRNA (miR)-150 expression and concurrent induction of its target gene, GPNMB, in neonatal rat lungs. This study aimed to test the hypothesis that soluble GPNMB (sGPNMB) promotes angiogenesis in the hyperoxic neonatal lungs. Wild-type (WT) or miR-150 knockout (KO) neonates, exposed to 95% O 2 for 3, 6, and 10 days, were evaluated for lung phenotypes, GPNMB protein expression in the lungs, and sGPNMB levels in the bronchoalveolar lavage. Angiogenic effects of sGPNMB were examined both in vitro and in vivo. After a 6-day exposure, similar analyses were performed in WT and miR-150 KO neonates during recovery at 7, 14, and 21 days. miR-150 KO neonates displayed an increased capillary network, decreased inflammation, and less alveolar damage compared with WT neonates after hyperoxia exposure. The early induction of GPNMB and sGPNMB were found in miR-150 KO neonates. The recombinant GPNMB, which contained a soluble portion of GPNMB, promoted endothelial tube formation in vitro and enhanced angiogenesis in vivo. The increased capillaries in the hyperoxic lungs of miR-150 KO neonates appeared dysmorphic. They were abnormally enlarged in size and occasionally laid at subepithelial regions in the alveoli. However, the lung architecture returned to normal during recovery, suggesting that abnormal vascularity during hyperoxia does not affect postnatal lung development. GPNMB plays an important role in angiogenesis during hyperoxia injury. Treatment with GPNMB may offer a novel therapeutic approach in reducing pathologic complications in bronchopulmonary dysplasia.

Endothelial microRNA-150 is an intrinsic suppressor of pathologic ocular neovascularization

“…In addition, lack of miR-150 significantly exacerbated CNV lesions in the laser-induced CNV model and increased sprouting in aortic ring and choroidal explants, further supporting an antiangiogenic effect of miR-150. These findings are consistent with another study showing increased lung angiogenesis in miR-150 −/− mice in a model of oxygen-induced neonatal lung injury (29). Although these data strongly support a primarily direct effect of vascular-enriched miR-150 on endothelial function and ocular angiogenesis, we cannot rule out potential contributions from circulating miR-150, which was found in monocytederived microvesicles to regulate target genes in the recipient ECs and affect pathological angiogenesis in tumor and diabetic models (30,31).…”

MicroRNA expression profiles and target prediction in neonatal Wistar rat lungs during the development of bronchopulmonary dysplasia

“…Bhaskaran et al ( 24 ) confirmed that one of the miR-150 targets was glycoprotein nonmetastatic melanoma protein b (GPNMB), which may participate in the regulation of angiogenesis. Narasaraju et al ( 26 ) further confirmed the regulatory role of miR-150 in angiogenesis in BPD. Dong et al ( 25 ) found that miR-29 expression was upregulated in BPD and suggested that miR-29 may suppress lung development by inhibiting Ntrk2.…”

Impaired Pulmonary Vascular Development in Bronchopulmonary Dysplasia

“…Several studies have also shown that epigenetic regulation by microRNA expression is aberrant in BPD [76, 77]. Transgenic miR-150 knockout mice demonstrate increased angiogenesis when exposed to neonatal hyperoxia that may be due to upregulation of glycoprotein non-metastatic melanoma protein B (GPNMB) [78]. Differential regulation of gene expression by these and other mechanisms may explain previous observations that mechanical ventilation and oxygen therapy increase antiangiogenic gene expression (thrombospondin-1, endoglin) and decrease expression of angiogenic genes (VEGFB, VEGFR2, Tie-2) [79, 80].…”