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 January 2, 2020; First 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 Transplantation

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 6

Apelin-17 analog treatment suppresses arterial vasculopathy and immune cell infiltration of heart transplants.

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Apelin-17 analog treatment suppresses arterial vasculopathy and immune c...
Apln+/y male hearts were transplanted into WT female recipients. Two weeks after transplantation the recipient mice were treated daily with saline or apelin-17 analog or with apelin-17 analog plus l-NAME; then the heart allografts were recovered at the time the graft heartbeat stopped, or at 6 weeks after transplantation. (A) Photomicrographs of transplanted hearts stained with van Gieson, immunostained for CD3, Mac-2, or EC CD31. Scale bars: 50 μm. (B) Quantitation as in Figure 2 of the intima area of graft arteries in heart recipients treated with saline (n = 8 biological replicates), apelin-17 analog (n = 9), or apelin-17 analog plus l-NAME (n = 5). (C) Quantitation of CD31+ microvessels in grafts of heart recipients treated with saline (n = 8 biological replicates), apelin-17 analog (n = 9), or apelin-17 analog plus l-NAME (n = 5). (D) Quantitation of immune cell infiltration in myocardium of grafts from heart recipients as in C. Mean ± SEM; *P < 0.05, **P < 0.01 by 1-way ANOVA with Bonferroni’s post hoc test. (E) Survival of heart allografts in mice treated with apelin-17 analog without (n = 9) or with l-NAME (n = 5 biological replicates) starting on day 14 after transplantation. **P < 0.01 by log rank. (F and G) Expression of endothelial repair (F) and proinflammatory (G) genes in microdissected coronary arteries from recipient mice treated with saline (n = 4 pairs) or apelin-17 analog (n = 5 pairs). Coronary artery data were analyzed by Mann-Whitney test. Mean ± SEM; *P < 0.05, **P < 0.02. (H and I) Expression of endothelial repair (H) and proinflammatory (I) genes in myocardium of heart grafts from recipient mice treated with saline (n = 8) or apelin-17 analog (n = 9). Mean ± SEM; **P < 0.01 by Student’s t test.