Endothelial Semaphorin 3F Maintains Endothelial Barrier Function and Inhibits Monocyte Migration

Abstract

In normal physiology, endothelial cells (ECs) form a vital barrier between the blood and underlying tissue controlling leukocyte diapedesis and vascular inflammation. Emerging data suggest that neuronal guidance cues, typically expressed during development, have roles outside the nervous system in vascular biology and immune responses. In particular, Class III semaphorins have been reported to affect EC migration and angiogenesis. While ECs express high levels of semaphorin 3F (SEMA3F), little is known about its function in mature ECs. Here we show that SEMA3F expression is reduced by inflammatory stimuli and increased by laminar flow. Endothelial cells exposed to laminar flow secrete SEMA3F, which subsequently binds to heparan sulfates on the surface of ECs. However, under pro-inflammatory conditions, reduced levels of SEMA3F make ECs more prone to monocyte diapedesis and display impaired barrier function as measured with an electric cell–substrate impedance sensing system and a microfluidic system. In addition, we demonstrate that SEMA3F can directly inhibit the migration of activated monocytes. Taken together, our data suggest an important homeostatic function for EC-expressed SEMA3F, serving as a mediator of endothelial quiescence.

Characterization of Class-3 Semaphorin Receptors, Neuropilins and Plexins, as Therapeutic Targets in a Pan-Cancer Study

“…SEMA3C and SEMA3D were reported to be able to transduce signals using other or additional PLXN receptors than PLXND1 such as PLXNB1 [ 24 , 31 , 32 ]. SEMA3F was reported to require a NRP and the presence of PLXNA1 and PLXNA3 to transduce signals in endothelial cells [ 33 , 34 ]. Upon semaphorin binding, PLXNs will trigger the activation of PLXN-associated receptor-type or cytoplasmic non-receptor-type tyrosine kinases (TKs) to elicit divergent semaphorin-dependent signaling pathways and functional outcomes [ 5 , 35 ].…”

Lysosomal Function and Axon Guidance: Is There a Meaningful Liaison?

“…Besides their role in axon guidance modulation, the SEMA3 family of proteins has been demonstrated to play an important function in vascular homeostasis also. In particular, SEMA3F seems to be involved in endothelial barrier homeostasis and monocyte migration [ 16 ]. Finally, semaphorins are known modulators of cancer cell behavior, such as glioblastoma cell growth, survival, invasiveness, and angiogenesis [ 17 ].…”

Endothelial Semaphorin 3fb regulates Vegf pathway-mediated angiogenic sprouting

“…Sema3F is highly expressed by cultured human and mouse endothelial cells [ 27 – 30 ] and in endothelial cells in scRNAseq databases [ 31 , 32 ]. SEMA3F typically signals through Neuropilin receptors (NRP) to modulate migration in cell culture models [ 30 , 33 ].…”