Control of vascular integrity via endothelial growth factor and integrin cell adhesion receptor pathways

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Sammanfattning

Vascular integrity is essential for proper vessel function, and for the maintenance of tissue and organ homeostasis. Endothelial cells (ECs) in the inner lining of the blood vessels form a barrier that dynamically regulates permeability across the vessel wall. Permeability via EC-EC junctions is transiently increased during inflammation, whereas abnormally or persistently elevated EC permeability promotes disease pathogenesis. For example, in sepsis, systemic capillary leakage compromises blood perfusion, and may lead to hypovolemic shock and multiorgan failure. Despite the significant amount of research on the mechanisms that control the EC barrier, no targeted therapies currently exist to seal the leaky vessels and maintain tissue perfusion. The aim of this study was to investigate how vascular permeability is controlled via an EC-derived growth factor angiopoietin-2 (ANGPT2), which is upregulated in various human diseases, including sepsis. ANGPT2 was found to signal via beta1-integrin, and therefore the function of endothelial beta1-integrin in vascular permeability was investigated. The results identified a novel signaling pathway, where ANGPT2–beta1-integrin signaling promotes EC permeability. Beta1-integrin was found to play a previously uncharacterized role in inflammation-induced vascular permeability, and an antibody against beta1-integrin inhibited vascular leakage, improved EC junction integrity and protected from cardiac failure in LPS-induced murine endotoxemia. Earlier studies have shown that ANGPT2 destabilizes blood vessel integrity in a context-dependent manner via its classical receptor TEK receptor tyrosine kinase (TIE2) on ECs. These studies have raised interest on ANGPT2 as a potential target in various diseases, including cancer and ocular neovascular diseases. This study revealed that ANGPT2 can promote EC destabilization independently of TIE2, which is downregulated during inflammation. These results suggest that a better understanding of the signaling function of ANGPT2 is necessary, in order to optimally target ANGPT2 in disease. This study also highlights the crucial role of endothelial beta1-integrin in controlling inflammation-induced EC permeability. The results showed that various inflammatory agents induced EC monolayer destabilization via beta1-integrin, manifested by the loss of junctional VE-cadherin, the formation of actin stress fibers, and altered EC-extracellular matrix (ECM) adhesions. The EC-ECM adhesions that formed in inflammation were elongated fibrillar adhesions that can be distinguished from focal adhesions by the presence of the adapter protein tensin-1. Furthermore, beta1-integrin promoted inflammation-induced EC contractility and reduced the EC barrier function. Importantly, targeting beta1-integrin using a monoclonal antibody, or via a heterozygous genetic deletion in the endothelium of gene-targeted mice decreased vascular leakage in LPS-induced murine endotoxemia. Notably, the beta1-integrin antibody was effective both as a prophylactic and as an intervention therapy, administered after the onset of systemic inflammation and vascular leakage, and its mechanism of action was independent of attenuating systemic inflammation, and of the vascular stabilizing function of TIE receptors. In summary, this thesis provides new knowledge on the mechanisms that lead to vascular leakage via ANGPT2 and beta1-integrin. Beta1-integrin was identified as a potentially universal regulator of EC permeability. A major finding was that targeting the EC beta1-integrin in a preclinical model of sepsis decreased vascular leakage, thereby improving cardiac function. The results of this thesis call for further studies in evaluating the translational potential of beta1-integrin mediated vascular permeability.
Originalspråkengelska
Handledare
  • Saharinen, Pipsa, Handledare
UtgivningsortHelsinki
Förlag
Tryckta ISBN978-951-51-5808-6
Elektroniska ISBN978-951-51-5809-3
StatusPublicerad - 2020
MoE-publikationstypG5 Doktorsavhandling (artikel)

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  • 3111 Biomedicinska vetenskaper

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