Abstract
Protein tyrosine phosphatases are essential modulators of angiogenesis and have been identified as novel therapeutic targets in cancer and anti-angiogenesis. The roles of atypical Phosphatase of Regenerative Liver (PRL) phosphatases in this context remain poorly understood. Here, we investigate the biological function of PRL phosphatases in developmental angiogenesis in the postnatal mouse retina and in cell culture. We show that endothelial cells in the retina express PRL-2 encoded by the Ptp4a2 gene, and that inducible endothelial and global Ptp4a2 mutant mice exhibit defective retinal vascular outgrowth, arteriovenous differentiation, and sprouting angiogenesis. Mechanistically, PTP4A2 deletion limits angiogenesis by inhibiting endothelial cell migration and the VEGF-A, DLL-4/NOTCH-1 signaling pathway. This study reveals the importance of PRL-2 as a modulator of vascular development.
Highlights
Protein tyrosine phosphatases are essential modulators of angiogenesis and have been identified as novel therapeutic targets in cancer and anti-angiogenesis
We evaluated Ptp4a1, Ptp4a2, and Ptp4a3 expression in the developing CNS using the Trans-omics Resource Database (VECTRDB; https:// markfsabbagh.shinyapps.io/vectrdb/; ref. 55), which contains scRNA-seq data from FACS-purified GFP-positive endothelial cells isolated from a postnatal day 7 (P7) Tie2-GFP mouse brain, to assess Ptp4a1, Ptp4a2, and Ptp4a3 expression in various brain endothelial cell subtypes
Knockout mice that we generated, we show that the loss of endothelial Phosphatase of Regenerative Liver (PRL)-2 function leads to impaired postnatal retinal angiogenesis, with effects on angiogenic sprouting, vessel stability, and arterial–venous specification
Summary
Protein tyrosine phosphatases are essential modulators of angiogenesis and have been identified as novel therapeutic targets in cancer and anti-angiogenesis. We show that endothelial cells in the retina express PRL-2 encoded by the Ptp4a2 gene, and that inducible endothelial and global Ptp4a2 mutant mice exhibit defective retinal vascular outgrowth, arteriovenous differentiation, and sprouting angiogenesis. PTP4A2 deletion limits angiogenesis by inhibiting endothelial cell migration and the VEGF-A, DLL-4/NOTCH1 signaling pathway. The vascular endothelial growth factor (VEGF) family has important roles in the angiogenic process. It has been shown that NOTCH-1/DLL-4 signaling plays a crucial role in vascular development and is involved in the tip–stalk cell crosstalk. DLL-4/NOTCH-1 signaling represents an important molecular link between sprouting angiogenesis and artery formation. The roles of tyrosine kinase receptors, such as VEGFR-2‚ in angiogenesis are well studied, little is known about the function of PTPs in these processes. The PRL phosphatases are intracellular phosphatases that are composed of three members, PRL-1, PRL-2, and PRL-3
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