Bending cilia sense flow forces during vascular development [with video]

Sensing mechanical forces is key to cardiovascular development but the mechanism explaining how endothelial cells sense flow forces remains unclear. The aim of this study was to address the mechanism of endothelial cell mechanotransduction through primary cilia by implementing live and high-resolution imaging of endothelial cilia during zebrafish vascular development.

HFSP Career Development Award holder Julien Vermot and colleagues
authored on Sat, 19 April 2014

While for many years cilia hardly attracted the interest of biologists, these long and thin cell surface structures are gradually gaining respectability. They have many essential functions at the organ and whole organism level. Those present in the nose, for example, are essential for odor perception, while in the inner ear they detect head movements and thus help maintain balance. When defective, numerous health problems can occur; obesity, fertility disorders, muscle, kidney, and lung problems have all been associated with the function of cilia. They also play an important role during embryonic development. Developmental malfunction can have serious consequences and eventually lead to a reversed arrangement of the internal organs.

Figure 1: Three dimensional reconstruction of an endothelial cilia after correlative light and 3D EM tomography.

Julien Vermot’s team at the IGBMC in Illkirch, France  focused on the role of cilia in endothelial cells, which form blood vessels during development. In zebrafish, a few hours after fertilization, most endothelial cells of the circulatory system are ciliated. The researchers demonstrated that the cilia are, in fact, mechanosensors that are highly sensitive to tiny variations in the motion of the blood cells circulating in the growing blood vessels. In blood vessels they bend in response to the flow and the angle of this bending was seen to be proportional to the force of the blood flow. This allows the low blood flow forces generated by the heart, which beats gently at early stages, to be detected by the endothelial cells. While they are absolutely essential to the early development of the vascular system, cilia were seen to disappear as the heart beat grows stronger and the blood flow becomes more powerful.

Figure 2: Cross section of the basal body of an endothelial cilia imaged through electron microsocopy.

Thanks to an innovative approach combining light and electron microscopy, Julien Vermot’s team could measure the deflection of the cilia depending on the strength of the flow and simultaneously reconstruct the 3D internal architecture of a cilium. This allowed them to predict the mechanical properties of cilium structure and highlight its extraordinary sensitivity. Indeed, cilia found on endothelial cells are three times more flexible than similar structures in the adult organism, such as those in the kidney, thus enabling them to detect very small variations in flow. At the cellular level, cilia bending results in an increase in the calcium concentration inside the cell, which is likely to activate signaling pathways necessary for correct vascular development.

For the first time in vivo, these results demonstrate the essential role of cilia on endothelial cells in early stages of development of the vascular system. They offer insight in to the understanding of blood vessel formation, a particularly important process in tumor progression. Indeed, just like healthy tissue, a tumor requires oxygen and nutrients to continue to grow and inducing the formation of new vessels is one way to achieve this. With further exploration, these results may also shed new light on the molecular mechanisms leading to atherosclerosis, a disease responsible for the majority of cardiovascular diseases in which endothelial cilia could be involved.

 

Reference

Endothelial Cilia Mediate Low Flow Sensing during Zebrafish Vascular Development. Goetz JG, Steed E, Ferreira RR, Roth S, Ramspacher C, Boselli F, Charvin G, Liebling M, Wyart C, Schwab Y, Vermot J. Cell Rep. 2014 Mar 13;6(5):799-808. doi: 10.1016/j.celrep.2014.01.032. Epub 2014 Feb 20.

Pubmed link

Link to Cell article