| First Author | Jiang X | Year | 2013 |
| Journal | J Mol Med (Berl) | Volume | 91 |
| Issue | 9 | Pages | 1081-93 |
| PubMed ID | 23797537 | Mgi Jnum | J:318988 |
| Mgi Id | MGI:6862217 | Doi | 10.1007/s00109-013-1063-8 |
| Citation | Jiang X, et al. (2013) Tie2-dependent VHL knockdown promotes airway microvascular regeneration and attenuates invasive growth of Aspergillus fumigatus. J Mol Med (Berl) 91(9):1081-93 |
| abstractText | Microvascular ischemia and infections are associated with the development of chronic rejection following lung transplantation. The von Hippel-Lindau protein (VHL) controls protein levels of hypoxia-inducible factors (HIFs), regulates vascular repair, and improves tissue perfusion. Here, we studied the role of VHL in microvascular repair by orthotopically transplanting tracheas into mice with VHL haplodeficiency in Tie2 lineage cells. We showed that VHL haplodeficiency prolonged airway microvascular perfusion and promoted tissue blood flow through the production of the angiogenic factors, SDF-1 and angiopoietin 1. VHL-haplodeficient pulmonary endothelial cells exhibited increased angiogenic activity, resistance to serum deprivation-induced cell death, and enhanced microvascular repair. By contrast, in recipient mice with HIF-1alpha deficiency in Tie2 lineage cells, microvascular repair was significantly diminished and suggested that recipient-derived HIF-1alpha normally participates in the repair of alloimmune-mediated microvascular damage. To evaluate the translational impact of our findings, we compared VHL-haplodeficient mice with wild-type controls using a model of Aspergillus airway infection. In 83% of the VHL-haplodeficient recipients, Aspergillus fumigatus was noninvasive in contrast to 75% of wild-type mice in which the mold was deeply invasive. Our study demonstrated that stabilization of HIF-1alpha in angiogenic cells, through Tie2 cell VHL haplodeficiency, promoted airway microvascular regeneration and vascular normalization and thereby minimized tissue ischemia and hypoxia. By also mitigating the virulence of A. fumigatus, a common pathogen and itself a risk factor for the development of lung transplant rejection, the selective enhancement of HIF-1alpha expression has the prospect of offering several novel therapeutic effects to transplant recipients. |
