Apelin directs endothelial cell differentiation and vascular repair following immune-mediated injury
Andrew G. Masoud, … , Gavin Y. Oudit, Allan G. Murray
Andrew G. Masoud, … , Gavin Y. Oudit, Allan G. Murray
Published November 18, 2019
Citation Information: J Clin Invest. 2020;130(1):94-107. https://doi.org/10.1172/JCI128469.
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Research Article Cardiology

Apelin directs endothelial cell differentiation and vascular repair following immune-mediated injury

Abstract

Sustained, indolent immune injury of the vasculature of a heart transplant limits long-term graft and recipient survival. This injury is mitigated by a poorly characterized, maladaptive repair response. Vascular endothelial cells respond to proangiogenic cues in the embryo by differentiation to specialized phenotypes, associated with expression of apelin. In the adult, the role of developmental proangiogenic cues in repair of the established vasculature is largely unknown. We found that human and minor histocompatibility–mismatched donor mouse heart allografts with alloimmune-mediated vasculopathy upregulated expression of apelin in arteries and myocardial microvessels. In vivo, loss of donor heart expression of apelin facilitated graft immune cell infiltration, blunted vascular repair, and worsened occlusive vasculopathy in mice. In vitro, an apelin receptor agonist analog elicited endothelial nitric oxide synthase activation to promote endothelial monolayer wound repair and reduce immune cell adhesion. Thus, apelin acted as an autocrine growth cue to sustain vascular repair and mitigate the effects of immune injury. Treatment with an apelin receptor agonist after vasculopathy was established markedly reduced progression of arterial occlusion in mice. Together, these initial data identify proangiogenic apelin as a key mediator of coronary vascular repair and a pharmacotherapeutic target for immune-mediated injury of the coronary vasculature.

Authors

Andrew G. Masoud, Jiaxin Lin, Abul K. Azad, Maikel A. Farhan, Conrad Fischer, Lin F. Zhu, Hao Zhang, Banu Sis, Zamaneh Kassiri, Ronald B. Moore, Daniel Kim, Colin C. Anderson, John C. Vederas, Benjamin A. Adam, Gavin Y. Oudit, Allan G. Murray

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Figure 2

Apelin loss exacerbates arterial vasculopathy and blunts endothelial repair.

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Apelin loss exacerbates arterial vasculopathy and blunts endothelial rep...
(A) Photomicrographs of coronary arteries from mouse heart transplants, with van Gieson stain to highlight the internal elastic lamina in black. Syngeneic male-to-male transplants have a single-cell layer of intima. Progressive expansion of the intima is evident from 2 weeks (top panels) to 6 weeks (bottom panels) after transplantation in allogeneic male to apelin WT female transplants, which is more marked among apelin-deficient male donor hearts. Scale bars: 50 μm. (B) Quantitation of intima area as a fraction of the area within the internal elastic lamina at 2 weeks and 6 weeks after transplantation among grafts as in Figure 1. (C) Microvessel density among freshly harvested donor reference hearts versus WT or apelin-deficient hearts from B recovered 6 weeks after transplantation. Mean ± SEM; *P < 0.05, **P < 0.01 by 1-way ANOVA with Bonferroni’s post hoc test. (D) ECs were transfected with scrambled or apelin siRNA, then plated at confluence. The monolayers were injured with a scratch wound, then stimulated with VEGF (50 ng/mL) or apelin-17 analog (1 μM) as indicated (n = 5 biological replicates in independent experiments). Mean ± SEM; *P < 0.05, **P < 0.01 by 1-way ANOVA with Bonferroni’s post hoc test. (E) ECs were transfected with scrambled or apelin siRNA, then plated at confluence. The monolayers were injured with multiple scratch wounds, then stimulated with VEGF (50 ng/mL) or mock-treated. Western immunoblot of EC lysates for ESM1. Representative of 3 biological replicates. (F) Quantitation of data in E (n = 3 biological replicates). Mean ± SEM; **P < 0.01 by 1-way ANOVA with Bonferroni’s post hoc test.