Abstract
Endothelial cells respond to different levels of fluid shear stress through adaptations of their mechanosensitivity. Currently, we lack a good understanding of how this contributes to sculpting of the cardiovascular system. Cerebral cavernous malformation (CCM) is an inherited vascular disease that occurs when a second somatic mutation causes a loss of CCM1/KRIT1, CCM2, or CCM3 proteins. Here, we demonstrate that zebrafish Krit1 regulates the formation of cardiac valves. Expression of heg1, which encodes a binding partner of Krit1, is positively regulated by blood-flow. In turn, Heg1 stabilizes levels of Krit1 protein, and both Heg1 and Krit1 dampen expression levels of klf2a, a major mechanosensitive gene. Conversely, loss of Krit1 results in increased expression of klf2a and notch1b throughout the endocardium and prevents cardiac valve leaflet formation. Hence, the correct balance of blood-flow-dependent induction and Krit1 protein-mediated repression of klf2a and notch1b ultimately shapes cardiac valve leaflet morphology.
Highlights
Biophysical forces including shear stress caused by blood-flow trigger activation of mechanotransduction pathways within endothelial cells (ECs), a process which causes cellular changes that contribute to the sculpting of vascular networks and of the heart (Baeyens and Schwartz, 2016; Haack and Abdelilah-Seyfried, 2016)
To test whether the regulation of heg1 or krit1 mRNAs responds to changes in blood-flow, we measured their expression levels using RT-qPCR in troponin T type 2a morphants that have a non-contractile heart and lack blood-flow (Sehnert et al, 2002)
Given that levels of heg1 mRNA expression are affected by blood-flow, we explored whether upregulation of Heg1 or Krit1 would have an impact on endothelial mechanotransduction pathways
Summary
Biophysical forces including shear stress caused by blood-flow trigger activation of mechanotransduction pathways within endothelial cells (ECs), a process which causes cellular changes that contribute to the sculpting of vascular networks and of the heart (Baeyens and Schwartz, 2016; Haack and Abdelilah-Seyfried, 2016). One well-studied example of a blood-flow-sensitive developmental process involves remodeling of endocardial cushions into cardiac valve leaflets in the zebrafish embryo (Beis et al, 2005; Pestel et al, 2016; Scherz et al, 2008; Steed et al, 2016). As zebrafish cardiac atrioventricular (AV) cushions are remodeled into AV valve leaflets, endocardial klf2a is highly expressed on the luminal side of the developing valve leaflet, which is exposed to blood-flow, whereas its expression is low on the abluminal side of the leaflet (Steed et al, 2016). The precise spatiotemporal regulation of Klf expression within cardiac valve
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
