Community Research and Development Information Service - CORDIS

  • European Commission
  • Projects and Results
  • Final Report Summary - ENDHOMRET (Endothelial homeostasis and dysfunction in metabolic-vascular retina disease: The role of endothelial cell-intrinsic and endothelial cell extrinsic inflammatory pathways)

ENDHOMRET Report Summary

Project ID: 281296
Funded under: FP7-IDEAS-ERC
Country: Germany

Final Report Summary - ENDHOMRET (Endothelial homeostasis and dysfunction in metabolic-vascular retina disease: The role of endothelial cell-intrinsic and endothelial cell extrinsic inflammatory pathways)

The focus of the project is the crosstalk between vascular inflammation and metabolism, with a special focus on metabolic-vascular disease, such as insulin resistance- and diabetes-related disorders, especially of the retina. Retinopathies, including diabetic retinopathy and retinopathy of prematurity are major causes of blindness in adults and infants, respectively, thereby representing a major health burden. Vascular inflammation associated with dysfunction of the vascular endothelium is a central component of the pathophysiology of metabolic-vascular disease. Endothelial dysfunction includes inflammatory changes of the endothelium as well as alterations in endothelial survival functions. Consistently, endothelial dysfunction is regulated by: (i) Endothelial cell-extrinsic pathways, which involve the interaction of the endothelium with inflammatory pathways; such pathways are activated in the ischemic tissue and may modulate leukocyte adhesiveness and recruitment as well as endothelial survival functions. (ii) Endothelial cell-intrinsic pathways, which regulate endothelial survival functions e.g. within the diabetic or ischemic retina microenvironment. The present project performed a thorough analysis of basic mechanisms of vascular inflammation, leukocyte-endothelial interactions and endothelial dysfunction and studied endothelial cell-extrinsic inflammatory pathways and endothelial cell-intrinsic pathways in the context of metabolic-vascular retina disease. We have identified several new aspects involved in vascular inflammation. Specifically, the endogenous endothelial-derived anti-inflammatory factor, Developmental endothelial locus-1 (Del-1) regulates inflammation and vascular function in the context of metabolic-vascular disease of the retina. Moreover, IL17-mediated downregulation of Del-1 regulates vascular inflammation and neuroinflammation, while Del-1 expression is positively regulated by resolvins, thereby indicating a resolvin/Del-1 anti-inflammatory axis. In addition, we identified that endothelial Junctional Adhesion Molecule-C (JAM-C) modulates the normalization of the vasculature in the course of vasoproliferative retinopathy, while it does not affect pathologic angiogenesis. Therefore, targeting JAM-C may provide a novel therapeutic approach for promoting revascularisation and vessel normalization in retinopathies. Furthermore, we uncovered novel pathways for the regulation of leukocyte-endothelial interactions in the context of vascular inflammation, mediated e.g. by TLR signaling. In addition, we have found that myeloid cells/microglia regulate endothelial survival functions in the diabetic as well as ischemic retina. Consistently, manipulation of the function of macrophages and microglial cells substantially regulated the outcome of vasoproliferative retinopathy. With regards to endothelial cell-intrinsic pathways we have studied the role of the DNA repair machinery and of homeostatic pathways as regulators of endothelial function in vasoproliferative retinopathy. Taken together this project identified the important role of different endothelial cell-extrinsic and –intrinsic pathways that are involved in endothelial dysfunction in vascular inflammatory pathologies, such as in the microenvironment of the diabetic and ischemic retina. Our findings gave rise to novel insights into crucial mechanisms of vascular inflammation as well as to processes underlying the pathogenesis of metabolic-vascular retina disease.

Reported by

Follow us on: RSS Facebook Twitter YouTube Managed by the EU Publications Office Top