Abstract
Background
Retinopathy of prematurity (ROP) is the leading cause of blindness in infants, and elevation of HIF-1α through the PI3K/Akt and ERK pathways is implicated in ROP pathogenesis. The mechanism of action of propranolol in ROP remains controversial. We investigated the effect of propranolol on ROP and explored its potential mechanisms of action in an oxygen-induced retinopathy (OIR) mouse model.
Methods
OIR mice were first treated with propranolol intraperitoneally, and the retina integrity was measured by FITC-dextran and hematoxylin-eosin staining. The expression of HIF-1α, VEGF, and key signaling pathway proteins was determined using real-time PCR and western blotting.
Results
FITC-dextran staining showed that propranolol treatment reduced damage to retinal morphology in OIR mice. Mice treated with propranolol showed a reduced number of nuclei of vascular endothelial cells penetrating the inner limiting membrane of the retina, confirming the therapeutic effect of propranolol on ROP. Further analysis showed that HIF-1α and PI3K/Akt/ERK pathway protein levels were significantly elevated in OIR mice. In contrast, propranolol treatment downregulated the expression of these proteins, indicating that the PI3K/Akt/ERK/HIF-1α axis is associated with propranolol-induced ROP alleviation.
Conclusions
Propranolol has a therapeutic function against ROP, likely through the downregulation of HIF-1α via the PI3K/Akt/ERK pathway.
Impact
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Propranolol can reduce the formation of abnormal retinal neovascularization in oxygen-induced retinopathy (OIR) models, and reduce leaking, tortuous, and abnormally expanding retinal blood vessels.
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Propranolol possibly improves OIR by inhibiting the activated ERK and HIF-1α pathways. Furthermore, propranolol may downregulate HIF-1α via the PI3K/Akt/ERK pathway to ameliorate retinopathy of prematurity.
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This study elucidated that the therapeutic effect of propranolol in OIR mice does not involve the VEGFR-2 pathway.
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Data availability
The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.
References
Lad, E. M., Hernandez-Boussard, T., Morton, J. M. & Moshfeghi, D. M. Incidence of retinopathy of prematurity in the United States: 1997 through 2005. Am. J. Ophthalmol. 148, 451–458 (2009).
Gilbert, C. Retinopathy of prematurity: a global perspective of the epidemics, population of babies at risk and implications for control. Early Hum. Dev. 84, 77–82 (2008).
Wolforth, L. M., Loo, S. W. & Sood, S. L. Retinopathy of prematurity and ethnicity in Hawai’i: a retrospective study (1996 - 2006) of medical records from Kapi’olani Medical Center for Women and Children. Hawaii J. Med. Public Health 75, 68–72 (2016).
Good, W. V. et al. The incidence and course of retinopathy of prematurity: findings from the Early Treatment for Retinopathy of Prematurity Study. Pediatrics 116, 15–23 (2005).
Dhingra, D. et al. Change in the incidence and severity of retinopathy of prematurity (ROP) in a neonatal intensive care unit in Northern India after 20 years: comparison of two similar prospective cohort studies. Ophthalmic. Epidemiol. 26, 169–174 (2019).
Liu, Q. et al. Incidence of retinopathy of prematurity in Southwestern China and analysis of risk factors. Med. Sci. Monit. 20, 1442–1451 (2014).
Luo, X. Q. et al. Prevalence of retinopathy of prematurity in some tertiary hospitals in Guangdong Province. Chin. J. Ocul. Fundus Dis. 26, 273–275 (2010).
Zhu, L. Incidence Rate and Risk Factors of Retinopathy of Prematurity from a Multicenter Study. (Fudan University, 2006).
Tian, N. The Screening and Results in the Analysis of Premature Retinopathy in the Panyu District of Guangzhou City. (Southern Medical University, 2013).
Blencowe, H., Lawn, J. E., Vazquez, T., Fielder, A. & Gilbert, C. Preterm-associated visual impairment and estimates of retinopathy of prematurity at regional and global levels for 2010. Pediatr. Res. 74, 35–49 (2013).
Solebo, A. L., Teoh, L. & Rahi, J. Epidemiology of blindness in children. Arch. Dis. Child 102, 853–857 (2017).
Mercurio, A. M. VEGF/neuropilin signaling in cancer stem cells. Int. J. Mol. Sci. 20, 490 (2019).
Wang, H. Anti-VEGF therapy in the management of retinopathy of prematurity: what we learn from representative animal models of oxygen-induced retinopathy. Eye Brain 8, 81–90 (2016).
Semenza, G. L. Hypoxia-inducible factor 1 (HIF-1) pathway. Sci. STKE 2007, cm8 (2007).
Miwa, Y. et al. Pharmacological HIF inhibition prevents retinal neovascularization with improved visual function in a murine oxygen-induced retinopathy model. Neurochem. Int. 128, 21–31 (2019).
Wang, P. et al. Protein Kinase B (Akt) promotes pathological angiogenesis in murine model of oxygen-induced retinopathy. Acta Histochem. Cytochem. 44, 103–111 (2011).
Di, Y., Zhang, Y., Nie, Q. & Chen, X. Ccn1/Cyr61-Pi3k/Akt signaling promotes retinal neovascularization in oxygen-induced retinopathy. Int. J. Mol. Med. 36, 1507–1518 (2015).
Di, Y., Zhang, Y., Yang, H., Wang, A. & Chen, X. The mechanism of Ccn1-enhanced retinal neovascularization in oxygen-induced retinopathy through Pi3k/Akt-Vegf signaling pathway. Drug Des. Devel. Ther. 9, 2463–2473 (2015).
Fukuda, R. et al. Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on map kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. J. Biol. Chem. 277, 38205–38211 (2002).
Ristori, C. et al. Role of the adrenergic system in a mouse model of oxygen-induced retinopathy: antiangiogenic effects of beta-adrenoreceptor blockade. Invest. Ophthalmol. Vis. Sci. 52, 155–170 (2011).
Dal Monte, M. et al. Eye drop propranolol administration promotes the recovery of oxygen-induced retinopathy in mice. Exp. Eye Res. 111, 27–35 (2013).
Yun, J. H. et al. Propranolol increases vascular permeability through pericyte apoptosis and exacerbates oxygen-induced retinopathy. Biochem. Biophys. Res. Commun. 503, 2792–2799 (2018).
Filippi, L. et al. Oral propranolol for retinopathy of prematurity: risks, safety concerns, and perspectives. J. Pediatr. 163, 1570–1577.e1576 (2013).
Filippi, L. et al. Study protocol: safety and efficacy of propranolol 0.2% eye drops in newborns with a precocious stage of retinopathy of prematurity (DROP-ROP-0.2%): a multicenter, open-label, single arm, phase II trial. BMC Pediatr. 17, 165 (2017).
Friedman, L. M. et al. Effect of propranolol in patients with myocardial infarction and ventricular arrhythmia. J. Am. Coll. Cardiol. 7, 1–8 (1986).
Huang, X. R., Wang, Y. J., Yang, G. R., Yang, Z. X. & Zhang, J. S. The effect of propranolol on oxygen-induced retinal neovascularization. Chin. J. Pediatr. 54, 131–136 (2016).
Ying, G. S., Bell, E. F., Donohue, P., Tomlinson, L. A. & Binenbaum, G. Perinatal risk factors for the retinopathy of prematurity in postnatal growth and ROP study. Ophthalmic. Epidemiol. 26, 270–278 (2019).
Gao, H.-C., Chen, C., Zhang, Y.-Q. & Zhang, J.-M. Progress on study of the risk factors of retinopathy of prematurity. Int. Eye Sci. 18, 80–83 (2018).
Weber, M. A., Drayer, J. I. & Kaufman, C. A. The combined alpha- and beta-adrenergic blocker labetalol and propranolol in the treatment of high blood pressure: similarities and differences. J. Clin. Pharm. 24, 103–112 (1984).
Andersson, O. K., Widgren, B. & Berglund, G. A 10-year follow-up of men with mild hypertension. bendroflumethiazide and propranolol give equal effect in treatment of high blood pressure. Lakartidningen 82, 1159–1162 (1985).
Chandraratna, P. A. Comparison of acebutolol with propranolol, quinidine, and placebo: results of three multicenter arrhythmia trials. Am. Heart J. 109, 1198–1204 (1985).
Huang, J., Jiang, D., Zhao, S. & Wang, A. Propranolol suppresses infantile hemangioma cell proliferation and promotes apoptosis by upregulating Mir-125b expression. Anticancer Drugs 30, 501–507 (2019).
Jamshidian-Tehrani, M. et al. Clinical and ultrasonographic evaluation of infantile periocular hemangioma treated with oral propranolol. Ophthalmic. Plast. Reconstr. Surg. 35, 484–486 (2019).
Osada, A., Araki, E., Yamashita, Y. & Ishii, T. Combination therapy of propranolol, levothyroxine, and liothyronine was effective in a case of severe consumptive hypothyroidism associated with infantile hepatic hemangioma. Clin. Pediatr. Endocrinol. 28, 9–14 (2019).
Huang, X., Wang, Y., Yang, G., Yang, Z. & Zhang, J. Effects of propranolol on oxygen-induced retinal neovascularization in mouse. Zhonghua Er Ke Za Zhi 54, 131–136 (2016).
Cammalleri, M. et al. The beta adrenergic receptor blocker propranolol counteracts retinal dysfunction in a mouse model of oxygen induced retinopathy: restoring the balance between apoptosis and autophagy. Front. Cell Neurosci. 11, 395 (2017).
Villalvilla, A. et al. Circulating endothelial progenitor cells are reduced in rat oxygen-induced retinopathy despite a retinal Sdf-1/Cxcr4 and VEGF proangiogenic response. Life Sci. 91, 264–270 (2012).
Pisani, F. et al. Potential role of the methylation of VEGF gene promoter in response to hypoxia in oxygen-induced retinopathy: beneficial effect of the absence of Aqp4. J. Cell Mol. Med. 22, 613–627 (2018).
Dong, L. et al. PTB-associated splicing factor inhibits IGF-1-induced VEGF upregulation in a mouse model of oxygen-induced retinopathy. Cell Tissue Res. 360, 233–243 (2015).
Stevens, M. & Oltean, S. Modulation of receptor tyrosine kinase activity through alternative splicing of ligands and receptors in the VEGF-A/VEGFR axis. Cells 8, 288 (2019).
Li, G. et al. VEGFR-2 inhibitor apatinib hinders endothelial cells progression triggered by irradiated gastric cancer cells-derived exosomes. J. Cancer 9, 4049–4057 (2018).
Mao, Y., Liu, X., Song, Y., Zhai, C. & Zhang, L. VEGF-A/VEGFR-2 and FGF-2/FGFR-1 but not PDGF-BB/PDGFR-Β play important roles in promoting immature and inflammatory intraplaque angiogenesis. PLoS One 13, e0201395 (2018).
McLeod, D. S. & Lutty, G. A. Targeting VEGF in canine oxygen-induced retinopathy – a model for human retinopathy of prematurity. Eye Brain 8, 55–65 (2016).
Liu, Z. et al. Endothelial adenosine A2a receptor-mediated glycolysis is essential for pathological retinal angiogenesis. Nat. Commun. 8, 584 (2017).
Jin, X. et al. Netrin-1 interference potentiates epithelial-to-mesenchymal transition through the Pi3k/Akt pathway under the hypoxic microenvironment conditions of non-small cell lung cancer. Int J. Oncol. 54, 1457–1465 (2019).
Hu, F., He, Z., Sun, C. & Rong, D. Knockdown of Grhl2 inhibited proliferation and induced apoptosis of colorectal cancer by suppressing the Pi3k/Akt pathway. Gene 700, 96–104 (2019).
Konstantinopoulos, P. A. et al. Olaparib and Α-specific Pi3k inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion phase 1b trial. Lancet Oncol. 20, 570–580 (2019).
Zhang, Z., Yao, L., Yang, J., Wang, Z. & Du, G. Pi3k/Akt and Hif-1 signaling pathway in hypoxia-ischemia (review). Mol. Med. Rep. 18, 3547–3554 (2018).
Jiang, B. H. & Liu, L. Z. Akt signaling in regulating angiogenesis. Curr. Cancer Drug Targets 8, 19–26 (2008).
Gao, S. et al. PEDF mediates pathological neovascularization by regulating macrophage recruitment and polarization in the mouse model of oxygen-induced retinopathy. Sci. Rep. 7, 42846 (2017).
Smith, L. E. et al. Oxygen-induced retinopathy in the mouse. Invest Ophthalmol. Vis. Sci. 35, 101–111 (1994).
Chen, J. et al. Propranolol inhibition of Β-adrenergic receptor does not suppress pathologic neovascularization in oxygen-induced retinopathy. Invest. Ophthalmol. Vis. Sci. 53, 2968–2977 (2012).
Romano, M. R. et al. Effects of bevacizumab on neuronal viability of retinal ganglion cells in rats. Brain Res. 1478, 55–63 (2012).
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G.Y., .YW., and L.L. drafted the manuscript. Y.L. and J.Z. analyzed the data. G.Y. and Y.W. supervised the study. Y.W. and S.S. designed the study and revised the manuscript critically for important intellectual content. S.S., Y.D., and P.Z. performed experiments. All authors read and approved the final manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.
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Su, S., Zou, P., Yang, G. et al. Propranolol ameliorates retinopathy of prematurity in mice by downregulating HIF-1α via the PI3K/Akt/ERK pathway. Pediatr Res 93, 1250–1257 (2023). https://doi.org/10.1038/s41390-022-02211-8
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DOI: https://doi.org/10.1038/s41390-022-02211-8
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