Endothelial cells transduce mechanical forces from blood flow into intracellular signals required for vascular homeostasis. Here we show that endothelial NOTCH1 is responsive to shear stress, and is necessary for the maintenance of junctional integrity, cell elongation, and suppression of proliferation, phenotypes induced by laminar shear stress. NOTCH1 receptor localizes downstream of flow and canonical NOTCH signaling scales with the magnitude of fluid shear stress. Reduction of NOTCH1 destabilizes cellular junctions and triggers endothelial proliferation. NOTCH1 suppression results in changes in expression of genes involved in the regulation of intracellular calcium and proliferation, and preventing the increase of calcium signaling rescues the cell–cell junctional defects. Furthermore, loss of Notch1 in adult endothelium increases hypercholesterolemia-induced atherosclerosis in the descending aorta. We propose that NOTCH1 is atheroprotective and acts as a mechanosensor in adult arteries, where it integrates responses to laminar shear stress and regulates junctional integrity through modulation of calcium signaling.
The cellular and mechanistic bases underlying endothelial regeneration of adult large vessels have proven challenging to study. Using a reproducible in vivo aortic endothelial injury model, we characterized cellular dynamics underlying the regenerative process through a combination of multi-color lineage tracing, parabiosis, and single-cell transcriptomics. We found that regeneration is a biphasic process driven by distinct populations arising from differentiated endothelial cells. The majority of cells immediately adjacent to the injury site re-enter the cell cycle during the initial damage response, with a second phase driven by a highly proliferative subpopulation. Endothelial regeneration requires activation of stress response genes including Atf3, and aged aortas compromised in their reparative capacity express less Atf3. Deletion of Atf3 reduced endothelial proliferation and compromised the regeneration. These findings provide important insights into cellular dynamics and mechanisms that drive responses to large vessel injury.
Our understanding of vascular morphogenesis and angiogenic growth has progressed considerably during the last few decades. Today the field has clarified the framework of interacting signaling pathways, intracellular regulatory genes and participating physical forces involved in the process of endothelial cell sprouting, lumen formation, and vascular remodeling. Nonetheless, once formed, vascular tubes also expand in width and length within the context of shear stress and tensional forces. Currently little information is available on how blood vessels perform this task or even what is the average half‐life of endothelial cells in the vascular wall. Using a combination of EdU incorporation, genetic tracing, rigorous quantification, and SILAM proteomics, our laboratory has gathered substantial information that sheds light into the cellular mechanisms and molecular players involved. The questions that will be addressed in this talk include: How does a vessel like the aorta expand in length and width while exposed to multiple physical forces? Do endothelial cells in an adult vessel divide to renew the endothelial lining or do [some] endothelial cells last for the lifetime of an individual? If endothelial cells proliferate: Is there a particular site/niche or do all cells all have equivalent capacity? Do endothelial cells have a finite number of cell divisions? What is the half‐life of endothelial cells in adult, normal blood vessels? What are the regulatory mechanisms involved in promoting vascular expansion? Taken together, we view this information as fundamental to our understanding the mechanisms controlling endothelial regeneration and their deregulations in settings like chronic/acute inflammation, aging, chronic diseases and physical trauma.Support or Funding InformationNIH/NHLBI R35HL140014This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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