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 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 1

Post-transplant vascular injury is associated with endothelial repair gene expression.

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Post-transplant vascular injury is associated with endothelial repair ge...
(A) Hearts recovered 2 weeks after transplantation were immunostained for the EC marker CD31 or cadherin 5. Myocardial microvessel density was quantitated (CD31+ [PECAM], left; cadherin 5+, right). Apln+/y to male recipients (n = 12 biological replicates) experienced reperfusion injury alone; Apln+/y (n = 15) and Apln–/y (n = 14) to Apln+/+ female recipients experienced reperfusion and chronic alloimmune injury. HPF, high-power field. (B) Gaps in the arterial endothelium in cross section (left) and the fraction of cleaved caspase-3+ (aCasp) immunostaining among the CD31+ arterial endothelium (right) were quantitated among the samples from A. Endothelial repair gene expression among transplanted hearts was determined by qRT-PCR, and expressed relative to nontransplanted control hearts. (C) Gene expression among microdissected coronary arteries at 2 or 6 weeks after transplantation. Samples were pooled in pairs for analysis (at 2 weeks: Apln+/y to male recipients, n = 6 pairs; Apln+/y, n = 8, and Apln–/y, n = 7, to Apln+/+ female recipients; at 6 weeks: Apln+/y to male recipients, n = 5 pairs; Apln+/y, n = 5, and Apln–/y, n = 5, to Apln+/+ female recipients). (D) Gene expression among myocardium samples after transplantation (at 2 weeks: Apln+/y to male recipients, n = 12 biological replicates; Apln+/y, n = 15, and Apln–/y, n = 14, to Apln+/+ female recipients; at 6 weeks: Apln+/y to male recipients, n = 9 biological replicates; Apln+/y, n = 10, and Apln–/y, n = 10, to Apln+/+ female recipients). (E) Hearts recovered 2 weeks after transplantation were immunostained for endothelial CD31 (green) and ESM1 (red, arrows). Medium-sized to larger arterial cross sections are represented in the top panels, whereas myocardial microvessels are in the bottom panels. Scale bars: 50 μm. (F) ESM1 immunofluorescence quantitation among heart transplants in E; Apln+/y to male recipients (n = 12 biological replicates), Apln+/y (n = 15) and Apln–/y (n = 14) to Apln+/+ female recipients. Mean ± SEM; *P < 0.05, **P < 0.01, by 1-way ANOVA with Bonferroni’s post hoc test.