Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

TRIM2 Selectively Regulates Inflammation-Driven Pathological Angiogenesis without Affecting Physiological Hypoxia-Mediated Angiogenesis

Nathan K.P. Wong
,
Emma L. Solly
ORCID logo ,
Richard Le
ORCID logo ,
Victoria A. Nankivell
,
Jocelyne Mulangala
,
Peter J. Psaltis
,
Stephen J. Nicholls
,
Martin K.C. Ng
,
Christina A. Bursill
ORCID logo ,
Joanne T.M. Tan
* ORCID logo
Version 1 : Received: 19 February 2024 / Approved: 19 February 2024 / Online: 19 February 2024 (08:33:17 CET)

A peer-reviewed article of this Preprint also exists.

Wong, N.K.P.; Solly, E.L.; Le, R.; Nankivell, V.A.; Mulangala, J.; Psaltis, P.J.; Nicholls, S.J.; Ng, M.K.C.; Bursill, C.A.; Tan, J.T.M. TRIM2 Selectively Regulates Inflammation-Driven Pathological Angiogenesis without Affecting Physiological Hypoxia-Mediated Angiogenesis. Int. J. Mol. Sci. 2024, 25, 3343. Wong, N.K.P.; Solly, E.L.; Le, R.; Nankivell, V.A.; Mulangala, J.; Psaltis, P.J.; Nicholls, S.J.; Ng, M.K.C.; Bursill, C.A.; Tan, J.T.M. TRIM2 Selectively Regulates Inflammation-Driven Pathological Angiogenesis without Affecting Physiological Hypoxia-Mediated Angiogenesis. Int. J. Mol. Sci. 2024, 25, 3343.

Abstract

Angiogenesis is a critical physiological response to ischemia but becomes pathological when dysregulated and driven excessively by inflammation. We recently identified a novel angiogenic role for tripartite-motif-containing protein 2 (TRIM2) whereby lentiviral shRNA-mediated TRIM2 knockdown impaired endothelial angiogenic functions in vitro. This study sought to determine whether these effects could be translated in vivo and to determine the molecular mechanisms involved. CRISPR/Cas9-generated Trim2–/– mice that underwent a periarterial collar model of inflammation-induced angiogenesis exhibited significantly less adventitial macrophage infiltration relative to wildtype (WT) littermates, concomitant with decreased mRNA expression of macrophage marker Cd68 and reduced adventitial proliferating neovessels. Mechanistically, TRIM2 knockdown in endothelial cells in vitro attenuated inflammation-driven induction of critical angiogenic mediators, including nuclear HIF-1α, and curbed the phosphorylation of downstream effector eNOS. Conversely, in a hindlimb ischemia model of hypoxia-mediated angiogenesis, there were no differences in blood flow reperfusion to the ischemic hindlimbs of Trim2–/– and WT mice despite a decrease in proliferating neovessels and arterioles. TRIM2 knockdown in vitro attenuated hypoxia-driven induction of nuclear HIF-1α but had no further downstream effects on other angiogenic proteins. Our study has implications for understanding the role of TRIM2 in the regulation of angiogenesis in both pathophysiological contexts.

Keywords

Inflammation; Ischemia; Neovascularization; HIF-1α; eNOS

Subject

Biology and Life Sciences, Cell and Developmental Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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