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bioRxiv · 10.1101/2025.02.12.637499

MicroRNA-34a suppresses KLF2 to promote pathological angiogenesis through the CXCR4/CXCL12 pathway in age-related macular degeneration

Colasanti, J. J.·Lin, J. B.·Terao, R.·Lee, T. J.·Santeford, A.·Apte, R. S.
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Abstract

Age-related macular degeneration (AMD), characterized by pathologic choroidal neovascularization (CNV), is a leading cause of vision loss in the elderly. Vascular endothelial growth factor A (VEGFa) antagonists can prevent acute vision loss, but high treatment burden and loss of efficacy with chronic therapy highlight the need to explore alternative mechanisms. Recently, microRNA-34a (miR-34a) has emerged as a key regulator in aging and age-related diseases, but its role in neovascular AMD is unclear. In an injury-induced murine CNV model, we discovered miR-34a promoted pathological angiogenesis, without altering expression of Vegfa or its receptor Kdr, the canonical regulators of CNV. Mechanistically, miR-34a directly targets and inhibits the transcription factor KLF2 thereby upregulating the pro-angiogenic factors CXCR4 and CXCL12. Finally, we show miR-34a exacerbates CNV in aged mice and is expressed in CNV lesions excised from wet AMD patients. These findings establish a causal link between the age-related miR-34a and neovascularization in AMD. TeaserIdentification of a molecular mechanism involved in the pathogenesis of a prevalent and debilitating age-related ocular disease.

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Colasanti, J. J., Lin, J. B., Terao, R., Lee, T. J., Santeford, A., Apte, R. S.. 2025-02-15. MicroRNA-34a suppresses KLF2 to promote pathological angiogenesis through the CXCR4/CXCL12 pathway in age-related macular degeneration. https://doi.org/10.1101/2025.02.12.637499

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