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

被引：49

作者：

Masoud, Andrew G. ^{[1
]}

Lin, Jiaxin ^{[2
,3
]}

Azad, Abul K. ^{[1
]}

Farhan, Maikel A. ^{[1
]}

Fischer, Conrad ^{[4
]}

Zhu, Lin F. ^{[2
]}

Zhang, Hao ^{[1
,5
]}

Sis, Banu ^{[6
]}

Kassiri, Zamaneh ^{[7
]}

Moore, Ronald B. ^{[2
]}

Kim, Daniel ^{[1
]}

Anderson, Colin C. ^{[2
,3
]}

Vederas, John C. ^{[4
]}

Adam, Benjamin A. ^{[6
]}

Oudit, Gavin Y. ^{[1
,5
]}

Murray, Allan G. ^{[1
]}

机构：

[1] Univ Alberta, Dept Med, Edmonton, AB, Canada

[2] Univ Alberta, Dept Surg, Edmonton, AB, Canada

[3] Univ Alberta, Dept Med Microbiol & Immunol, Edmonton, AB, Canada

[4] Univ Alberta, Dept Chem, Edmonton, AB, Canada

[5] Mazankowski Heart Inst, Edmonton, AB, Canada

[6] Univ Alberta, Dept Lab Med & Pathol, Edmonton, AB, Canada

[7] Univ Alberta, Dept Physiol, Edmonton, AB, Canada

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2020年 / 130卷 / 01期

关键词：

CARDIAC ALLOGRAFT VASCULOPATHY; INTERFERON-GAMMA; INTERNATIONAL SOCIETY; T-CELLS; RECEPTOR; HEART; TRANSPLANTATION; EXPRESSION; ANTIGEN; APJ;

D O I：

10.1172/JCI128469

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页码：94 / 107

页数：14

共 60 条

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