From vascular tissue mechanics to Klf2 transcription factor-induced angiogenesis

• Applicant: Professor Dr. Salim Seyfried
• Subject Area: Developmental Biology ; Evolutionary Cell and Developmental Biology (Zoology) ; Cardiology, Angiology ; Cell Biology
• Term: from 2014 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 258969466

In the vascular system, mechanotransduction pathways are activated in response to mechanical stimuli induced by blood flow or basement membrane stiffness and play important roles during the development and in the homeostasis of vascular tissues. Endothelial cells have numerous mechanotransducers including cadherins at cell-cell junctions and integrins at cell-matrix adhesions. The French partner recently demonstrated that the CCM complex, depleted in a hereditary and sporadic cerebrovascular disease (the Cerebral Cavernous Malformation pathology), functions as a node between VE-cadherin-dependent cell-cell interactions and beta1 integrin-dependent cell-ECM adhesion. Upon loss of the CCM protein complex, extracellular matrix mechanics is changed due to beta1 integrin activation and feeds back onto endothelial cells by weakening VE-cadherin-mediated cell-cell adhesion and by raising endothelial permeability. The German partner demonstrated that the mechanosensitive transcription factor Klf2 is upregulated in zebrafish ccm2 mutant embryos and that knocking down Klf2 restores normal cardiovascular development. Collaboratively, both partners found that beta1 integrin is involved in the upregulation of Klf2 expression. High expression levels of Klf2 contribute to the ccm mutant phenotype in zebrafish through induction of Egfl7, an ECM-associated protein, which functions as a negative regulator of Notch signaling and activator of beta3 integrin signaling. Our ongoing collaboration supports the hypothesis that the activation of an angiogenesis program upon loss of CCM proteins might be orchestrated by beta1 and beta3 integrin signaling, which in turn stimulates the proangiogenic Klf2 mechanosensitive response. First, this grant proposal aims at elucidating the contractile and signaling pathways by which beta1 integrin regulates the Klf2 mechanotransduction pathway during development and under CCM pathophysiological conditions. Secondly, we will investigate the mechanism(s) by which Klf2 signaling regulates endoMT processes and endothelial stability. Our collaboration brings together the power of genetics and developmental biology of the zebrafish model with the in-depth mechanistic approach of in vitro controlled cell culture associated with innovative biophysical studies. This project is an interdisciplinary approach that aims at investigating the role of mechanotransduction in cardiovascular development and in the CCM disease, which is an associated pathology of the cerebrovasculature.

• DFG Programme: Research Grants
• International Connection: France
• Participating Person: Dr. Corinne Albiges-Rizo