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Eph receptors and ephrins in angiogenesis: Regulation through hypoxia

English title Eph receptors and ephrins in angiogenesis: Regulation through hypoxia
Applicant Huynh-Do Uyen
Number 105871
Funding scheme Project funding
Research institution Respiratory Medicine Department Universitätsklinik Inselspital
Institution of higher education University of Berne - BE
Main discipline Pathophysiology
Start/End 01.10.2004 - 31.12.2007
Approved amount 260'000.00
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All Disciplines (2)

Discipline
Pathophysiology
Cellular Biology, Cytology

Keywords (6)

Eph receptors; ephrins; angiogenesis; hypoxia; HIF-1alpha; skin flap

Lay Summary (English)

Lead
Lay summary
BACKGROUND. Eph receptors are a unique family of receptor tyrosine kinases that play critical roles in embryonic patterning, neuronal targeting and vascular development. The ligands for Eph receptors are the ephrins, which share the distinctive property of being membrane-bound. In the adult, Eph receptors have been shown to be upregulated in tumor tissues and to be involved in pathological neovascularization. In spite of the wealth of information correlating cell transformation with increased expression of Eph receptors, the molecular mechanisms underlying the roles of the Ephs in tumor formation, progression and metastasis have only started to emerge.AIM OF THE STUDY. The central hypothesis of our project is that hypoxia upregulates the expression of EphBs and their ephrinBs ligands. The goal of the proposed studies was therefore 1)to confirm preliminary in vitro and in vivo results showing evidence for a hypoxia-dependent regulation of EphB4 and ephrinB12)to investigate the underlying molecular mechanisms and3)to characterize the role of EphBs / ephrinBs in the hypoxia response in vivo, focussing on two different organ systems: the skin and the kidney. RESULTS. The project has been divided into two parts:1) Characterization of the role of Eph receptors and ephrins in dermal capillary repair and wound healing, using a mouse skin flap model of local tissue hypoxia. We successfully established this new model, which allowed us to continuously monitor the local oxygen tension, metabolism as well as histologic changes due to hypoxia. We showed that local hypoxia upregulates the tissue expression of EphB receptors and ephrins within 12 hours. Furthermore, using RNA interference, we showed that this effect was mediated by the transcription factor HIF-1 alpha. Ref: Vihanto et al, FASEB J 2005 Oct;19(12):1689-91. 2) Assessment of the role of EphBs / ephrinBs in the renal response to hypoxia, using a rat model of renal segmental infarction. Here we induced regional hypoxia by renal artery branch ligation, and studied its effect on cell morphology, induction of HIF, EphBs / ephrinBs, as well as capillary proliferation. We showed that Eph receptors and ephrins were upregulated not only in the endothelial but also tubular epithelial cells. These findings suggest that Eph receptors are important not only for capillary repair but also for tubular regeneration following acute hypoxic injury to the kidney. Ref: Abstract, ASN meetnig 2007 PERSPECTIVE. Dissecting the mechanisms underlying Eph/ephrin regulation in the skin will better delineate their role in skin angiogenesis and wound healing. On the other hand, the renal segmental infarction model will be the first in vivo model to date to define the role of Ephs / ephrins in the kidney response to hypoxia.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
118369 Renal angiogenesis in development and disease states: Role of Eph receptors and ephrins 01.01.2008 Project funding

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