Abstract

AngII and TGF-β interact in development of thoracic and abdominal aortic diseases, although there are many facets of this interaction that have not been clearly defined. The aim of the present study was to determine the effects of TGF-β neutralization on AngII induced-aortic pathologies. Male C57BL/6J mice were administered with either a rabbit or mouse TGF-β neutralizing antibody and then infused with AngII. The rabbit TGF-β antibody modestly reduced serum TGF-β concentrations, with no significant enhancements to AngII-induced aneurysm or rupture. Administration of this rabbit TGF-β antibody in mice led to high serum titers against rabbit IgG that may have attenuated the neutralization. In contrast, a mouse TGF-β antibody (1D11) significantly increased rupture in both the ascending and suprarenal aortic regions, but only at doses that markedly decreased serum TGF-β concentrations. High doses of 1D11 antibody significantly increased AngII-induced ascending and suprarenal aortic dilatation. To determine whether TGF-β neutralization had effects in mice previously infused with AngII, the 1D11 antibody was injected into mice that had been infused with AngII for 28 days and were observed during continued infusion for a further 28 days. Despite near ablations of serum TGF-β concentrations, the mouse TGF-β antibody had no effect on aortic rupture or dimensions in either ascending or suprarenal region. These data provide further evidence that AngII-induced aortic rupture is enhanced greatly by TGF-β neutralization when initiated before pathogenesis.

Document Type

Article

Publication Date

4-22-2016

Notes/Citation Information

Published in PLOS ONE, v. 11, no. 4, e0153811, p. 1-16.

© 2016 Chen et al.

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Digital Object Identifier (DOI)

https://doi.org/10.1371/journal.pone.0153811

Funding Information

National Marfan Foundation: http://www.marfan.org/?gclid=CNKUmZ3frMoCFYwvgQodAqMGTQ, National Institutes of Health - HL 107319 http://www.nih.gov/.

journal.pone.0153811.s001.PDF (65 kB)
S1 Fig. Representative images of (A) ascending aortic and (B) abdominal aortic rupture in mice infused with AngII.

journal.pone.0153811.s002.PDF (96 kB)
S2 Fig. Experimental design for Study #1: Inhibition of TGF-β using a rabbit polyclonal IgG in male normolipidemic AngII-infused mice.

journal.pone.0153811.s003.PDF (97 kB)
S3 Fig. Experimental design for Study #2, 3: Inhibition of TGF-β using a mouse monoclonal IgG (1D11) in male normolipidemic AngII-infused mice.

journal.pone.0153811.s004.PDF (100 kB)
S4 Fig. Experimental design for Study #4: Inhibition of TGF-β using a mouse monoclonal IgG (1D11) in male normolipidemic mice previously infused with AngII.

journal.pone.0153811.s005.PDF (105 kB)
S5 Fig. Diameter measurements of aortic regions in vivo imaged by ultrasound.

journal.pone.0153811.s006.PDF (133 kB)
S6 Fig. Measurement of the abdominal aorta diameter.

journal.pone.0153811.s007.PDF (88 kB)
S7 Fig. Measurement of the ascending aorta intimal area.

journal.pone.0153811.s008.PDF (569 kB)
S8 Fig. Images of ascending aortas ex vivo from AngII-infused mice in Study #1: Rabbit TGF-β neutralizing IgG experiment.

journal.pone.0153811.s009.PDF (1071 kB)
S9 Fig. Images of abdominal aortas ex vivo from AngII-infused mice in Study #1: Rabbit TGF-β neutralizing IgG experiment.

journal.pone.0153811.s010.PDF (2016 kB)
S10 Fig. Images of ascending aortas ex vivo from saline or AngII-infused mice in Study #2: Mouse TGF-β neutralizing IgG experiment.

journal.pone.0153811.s011.PDF (1810 kB)
S11 Fig. Images of abdominal aortas ex vivo from saline or AngII-infused mice in Study #2: Mouse TGF-β neutralizing IgG experiment.

journal.pone.0153811.s012.PDF (2196 kB)
S12 Fig. Baseline and Day 4 images of ascending aortas in vivo from mice infused with AngII and injected with mouse TGF-β neutralizing or control IgG.

journal.pone.0153811.s013.PDF (2150 kB)
S13 Fig. Baseline and Day 4 images of suprarenal aortas in vivo from mice infused with AngII for 4 days and injected with mouse TGF-β neutralizing or control IgG.

journal.pone.0153811.s014.PDF (1104 kB)
S14 Fig. Images of ascending aortas ex vivo from mice in Study #3: Injection of a low or high dose of mouse TGF-β neutralizing IgG.

journal.pone.0153811.s015.PDF (1493 kB)
S15 Fig. Images of abdominal aortas ex vivo from mice in Study #3: Injection of a low or high dose of mouse TGF-β neutralizing IgG.

journal.pone.0153811.s016.PDF (549 kB)
S16 Fig. Images of ascending aortas ex vivo from mice in Study #4.

journal.pone.0153811.s017.PDF (662 kB)
S17 Fig. Images of abdominal aortas ex vivo from mice in Study #4.