The Splicing Factor Kinase SRPK1 Is a Therapeutic Target for Peripheral Vascular Disease

Authors

• Sohni Ria Bhalla
• Mussarat Wahid
• Jason O Amartey
• Amira Zawia
• Federica Riu
• Yizhuo Gao
• Jyoti Agrawal
• Amy P Lynch
• Maria J C Machado
• Tom Hawtrey
• Ryosuke Kikuchi
• Kathryn R Green
• Lydia Teboul
• Claire Allen
• Zoe Blackley
• Keerthana Rajaji
• Jennifer Batson
• Steven J Harper
• Sebastian Oltean
• Winfried Amoaku
• Andrew V Benest
• Jonathan C Morris
• Bruce Braithwaite
• David O Bates

Language

English

Publication Date

8-1-2025

Journal

American Journal of Physiology-Heart and Circulatory Physiology

DOI

10.1152/ajpheart.00564.2024

PMID

40588360

Abstract

In peripheral arterial disease (PAD), antiangiogenic VEGF-A165b isoform overexpression in monocytes contributes to impaired collateralization. Serine-arginine protein-kinase-1 (SRPK1) regulates VEGF splicing. To determine whether SRPK1 controlled monocytic VEGF, impairing collateralization, we investigated SRPK1 inhibition and monocyte-specific knockout in mouse models of and in human monocytes from PAD. VEGF-A165b activity was measured by coculture of monocytes from patients with PAD with endothelial cells with SRPK1 inhibition. Mice with impaired revascularization due to soluble-frizzled-related-protein-5 knockout (Sfrp5-/-), monocyte-specific Wnt5a gain-of-function (LysM-Wnt5aGOF), or obese mice on a high-fat high-sucrose (HF/HS) diet were subjected to femoral artery ligation and treated with a SRPK1 inhibitor. We generated an SRPK1 conditional knockout and crossed it with monocyte-specific (LysM-Cre) driver line to specifically knockout SRPK1 in monocyte lineages. Blood flow was measured by laser speckle imaging before, and for 28 days after surgery. Monocytes from patients with PAD significantly inhibited endothelial cell migration, which was reversed by an anti-VEGF-A165b antibody. Surprisingly, migration was stimulated by SRPK1 inhibition, switching splicing from VEGF-A165b to VEGF-A165a. In Sfrp5-/-, LysM-Wnt5aGOF, and HF/HS mouse models of PAD, blood flow was improved by SRPK1 inhibition. Impaired revascularization in LysM-Wnt5aGOF mice was rescued in LysM-Wnt5aGOF:SRPK1MoKO mice, which had a phenotypic shift toward M2 macrophages. Impaired blood flow recovery was also rescued in obese-SRPK1MoKO mice. VEGF splicing in monocytes is regulated differently from VEGF splicing in epithelial or cancer cells suggesting that control of splicing is dependent on cell type and/or environment. SRPK1 inhibition enhances collateralization in mice, and in human in vitro models of monocyte-dependent impaired angiogenesis.NEW & NOTEWORTHY A novel potential treatment for peripheral arterial disease (PAD) is described. Inhibition of SRPK1, or knockout in monocytes, induces angiogenesis by preventing splicing to antiangiogenic VEGF (VEGF-A165b) in patients and animal models. In PAD, monocyte splicing control is different from other cell types and SRPK1 inhibition by drug-like compounds can alter macrophage phenotype and reverse PAD in mice. A new cell-specific SRPK1-LoxP mouse is described.

Keywords

Animals, Humans, Monocytes, Mice, Knockout, Peripheral Arterial Disease, Vascular Endothelial Growth Factor A, Protein Serine-Threonine Kinases, Disease Models, Animal, Wnt-5a Protein, Mice, Male, Protein Kinase Inhibitors, Human Umbilical Vein Endothelial Cells, Neovascularization, Physiologic, Mice, Inbred C57BL, Female, Cell Movement, Endothelial Cells, Cells, Cultured, VEGF, angiogenesis, peripheral artery disease, splicing

Published Open-Access

yes

Recommended Citation

Bhalla, Sohni Ria; Wahid, Mussarat; Amartey, Jason O; et al., "The Splicing Factor Kinase SRPK1 Is a Therapeutic Target for Peripheral Vascular Disease" (2025). Faculty, Staff and Students Publications. 8505.
https://digitalcommons.library.tmc.edu/baylor_docs/8505