Adenovirus-mediated HIF-1α gene transfer promotes repair of mouse airway allograft microvasculature and attenuates chronic rejection
Xinguo Jiang, Mohammad A. Khan, Wen Tian, Joshua Beilke, Ramesh Natarajan, Jon Kosek, Mervin C. Yoder, Gregg L. Semenza, Mark R. Nicolls
Xinguo Jiang, Mohammad A. Khan, Wen Tian, Joshua Beilke, Ramesh Natarajan, Jon Kosek, Mervin C. Yoder, Gregg L. Semenza, Mark R. Nicolls
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Research Article

Adenovirus-mediated HIF-1α gene transfer promotes repair of mouse airway allograft microvasculature and attenuates chronic rejection

Abstract

Chronic rejection, manifested as small airway fibrosis (obliterative bronchiolitis [OB]), is the main obstacle to long-term survival in lung transplantation. Recent studies demonstrate that the airways involved in a lung transplant are relatively hypoxic at baseline and that OB pathogenesis may be linked to ischemia induced by a transient loss of airway microvasculature. Here, we show that HIF-1α mediates airway microvascular repair in a model of orthotopic tracheal transplantation. Grafts with a conditional knockout of Hif1a demonstrated diminished recruitment of recipient-derived Tie2+ angiogenic cells to the allograft, impaired repair of damaged microvasculature, accelerated loss of microvascular perfusion, and hastened denudation of epithelial cells. In contrast, graft HIF-1α overexpression induced via an adenoviral vector prolonged airway microvascular perfusion, preserved epithelial integrity, extended the time window for the graft to be rescued from chronic rejection, and attenuated airway fibrotic remodeling. HIF-1α overexpression induced the expression of proangiogenic factors such as Sdf1, Plgf, and Vegf, and promoted the recruitment of vasoreparative Tie2+ cells. This study demonstrates that a therapy that enhances vascular integrity during acute rejection may promote graft health and prevent chronic rejection.

Authors

Xinguo Jiang, Mohammad A. Khan, Wen Tian, Joshua Beilke, Ramesh Natarajan, Jon Kosek, Mervin C. Yoder, Gregg L. Semenza, Mark R. Nicolls

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Figure 4

HIF-1α gene transfer prolongs microvascular perfusion of airway allograft and alleviates tissue hypoxia.

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HIF-1α gene transfer prolongs microvascular perfusion of airway allograf...
(A) Vascular perfusion of AdLacZ control adenovirus vector–treated allografts is lost at day 10, day 12, and day 14, followed by partial revascularization at day 21. However, perfusion of AdCA5-treated allografts is maintained at both day 10 and day 12, followed by partial loss at day 14 and near complete revascularization at day 21. (B) Percentage of perfusion area of AdLacZ- or AdCA5-treated allografts was calculated. (n = 4–6; *P < 0.05). (C) AdCA5-treated allografts have higher tissue pO2 levels compared with AdLacZ-treated grafts. (n = 4–6; *P < 0.05 at individual time points). (D) FITC-conjugated lectin perfusion and laminin staining show that AdCA5-treated chronically rejected day-21 allografts (lower panel) have better laminin-invested vessels (arrows) than AdLacZ-treated grafts (top panel). (E) FITC-conjugated lectin perfusion and α-SMA staining show that AdCA5-treated chronically rejected day-21 allografts (lower panel) have more pericyte-covered vessels (arrows) than AdLacZ-treated grafts (top panel). Scale bars: 100 μm (A); 20 μm (D and E). Data are shown as mean ± SEM.