Nature. The direct mechanical sensor of endothelial cells- the guided receptor nerve plexin D1.

This paper reports that endothelial cells are constantly impacted by blood flow, including the friction of fluid shear stress (depending on the geometry of blood vessels), which may be protective or pathogenic to endothelial cells.when these forces are in disorder, they may lead to up-regulation of pro-inflammatory genes and even be related to atherosclerotic lesions. However, under normal physiological conditions, this force also plays a role in the reconstruction of cytoskeleton and the orderly arrangement of endothelial cells in the flow direction [1].endothelial cell mechanical sensor is the first sensor to respond to the changes of mechanical environment.the importance of shear stress in the development and function of cardiovascular system has inspired people to explore the mechanical sensor of endothelial cells.plexins are a class of cellular receptors with a series of important functions in axon guidance, tumor progression and immune cell regulation.it is known that plexins play a role in binding cells or free state together with other co receptors through binding with ligands (semaphorin ligands), thus stimulating intracellular signal transmission and leading to a series of changes in cytoskeleton and cell adhesion [2].on February 6, 2020, Ellie tzima, from Oxford University, UK, published an article entitled the guidance receptor plexin D1 is a mechanosensor in endothelial cells.we found that plexin D (plxnd1) plays an important role in the pathogenesis of mechanical induction and mechanical induction related diseases.the authors found that plxnd1 is indispensable for endothelial cells to respond to shear stress in vivo and in vitro, and regulate the specific distribution of atherosclerotic plaque.the authors first silenced the expression of plxnd1 in bovine aortic endothelial cells.it was found that silencing the expression of plxnd1 could inhibit the activation of Akt, ERK1 / 2 and eNOS, and inhibit the expression of key downstream proteins KLF2, KLF4, proinflammatory factors CCL2 and VCAM1.using sema3e to block antibody confirmed that plxnd1 mechanical transduction is independent of its ligand sema3e.the plxnd1 silenced bovine aortic endothelial cells could not respond to shear stress, resulting in disordered arrangement of actin.these all indicate that plxnd1 is a key mediating protein in endothelial cells responding to shear stress.next, the authors further verified the plxnd1 knockout mice by endothelial cells.in gene knockout mice, the strength of actin stress fibers decreased and the elongation of endothelial cells decreased.the authors used apoE − / − mice to explore the effect of plxnd1 on atherosclerosis. in plxnd1 knockout mice, the plaque burden of descending aorta was increased, and the endothelial cells of mice could not respond to shear stress and regulate the distribution of specific sites of atherosclerosis. next, the authors used a magnetic system to exert tension on the paramagnetic beads containing antibodies to recognize plxnd1 extracellular domain, proving that plxnd1 is not only a participant in the induction of shear stress, but also a direct sensor of shear stress. the authors overexpressed each molecule in the mechanical induction complex in COS-7 cell line, and analyzed the role of plxnd1 in the mechanical induction complex by immunoprecipitation, and verified that plxnd1 is a specific and direct shear stress receptor. the authors analyzed the extracellular domain of plxnd1 by negative staining electron microscopy, and found that the main conformation of plxnd1 is ring, and it can also be bent into a more open conformation [3]. the author further explored the relationship between plxnd1's two different conformations and functions. The mutant plxnd1 (y517c / a1135c) was constructed to form disulfide bonds between domains 1 and 9 of the extracellular domain of plxnd1 to stabilize the cyclic conformation of plxnd1. it was found that the ring structure of plxnd1 could maintain its ligand dependent signal transduction function, but it would damage its ability to induce shear stress. in conclusion, plxnd1 in endothelial cells is a direct shear stress sensor and plays an indispensable role in the mechanoreceptor complex. plxnd1 performs its two roles as a ligand or shear stress receptor by using two different molecular conformations. although mechanical sensing is very important in biology, our understanding of it is still limited. this paper identified mechanical sensors in endothelial cells and provided a model for understanding ligand dependence and how mechanical signals are transmitted through a single protein. (1) givens, C. & amp; tzima, e. endothelial mechanisation: does one sensor fit all? Antioxid. Redox signal. 25, 373 – 388 (2016). 2. Sakurai, A. et al. Semaphorin 3E initiates antigeogenic signaling through plexin D1 by regulating ARF6 and R-Ras. Mol. cell. Biol. 30, 3086–3098 (2010).3. Kong, Y. et al. Structural basis for plexin activation and regulation. Neuron 91, 548–560(2016).