HarnessingEGLN1Gene Editing to Amplify HIF-1α and Enhance Human Angiogenic Response

Author:

Shams Shahin,Stilhano Roberta S.,Silva Eduardo A.

Abstract

ABSTRACTTherapeutic angiogenesis has been the focus of hundreds of clinical trials but approval for human treatment remains elusive. Current strategies often rely on the upregulation of a single proangiogenic factor, which fails to recapitulate the complex response needed in hypoxic tissues. Hypoxic oxygen tensions dramatically decrease the activity of hypoxia inducible factor prolyl hydroxylase 2 (PHD2), the primary oxygen sensing portion of the hypoxia inducible factor 1 alpha (HIF-1α) proangiogenic master regulatory pathway. Repressing PHD2 activity increases intracellular levels of HIF-1α and impacts the expression of hundreds of downstream genes directly associated with angiogenesis, cell survival, and tissue homeostasis. This study explores activating the HIF-1α pathway throughSpCas9 knockout of the PHD2 encoding geneEGLN1as an innovativein situtherapeutic angiogenesis strategy for chronic vascular diseases. Our findings demonstrate that even low editing rates ofEGLN1lead to a strong proangiogenic response regarding proangiogenic gene transcription, protein production, and protein secretion. In addition, we show that secreted factors ofEGLN1edited cell cultures may enhance human endothelial cell neovascularization activity in the context of proliferation and motility. Altogether, this study reveals thatEGLN1gene editing shows promise as a potential therapeutic angiogenesis strategy.

Publisher

Cold Spring Harbor Laboratory

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