Intriguing Roles for Endothelial ADAM10/Notch Signaling in the Development of Organ-Specific Vascular Beds

Abstract

The vasculature is a remarkably interesting, complex, and interconnected organ. It provides a conduit for oxygen and nutrients, filtration of waste products, and rapid communication between organs. Much remains to be learned about the specialized vascular beds that fulfill these diverse, yet vital functions. This review was prompted by the discovery that Notch signaling in mouse endothelial cells is crucial for the development of specialized vascular beds found in the heart, kidneys, liver, intestines, and bone. We will address the intriguing questions raised by the role of Notch signaling and that of its regulator, the metalloprotease ADAM10, in the development of specialized vascular beds. We will cover fundamentals of ADAM10/Notch signaling, the concept of Notch-dependent cell fate decisions, and how these might govern the development of organ-specific vascular beds through angiogenesis or vasculogenesis. We will also consider common features of the affected vessels, including the presence of fenestra or sinusoids and their occurrence in portal systems with two consecutive capillary beds. We hope to stimulate further discussion and study of the role of ADAM10/Notch signaling in the development of specialized vascular structures, which might help uncover new targets for the repair of vascular beds damaged in conditions like coronary artery disease and glomerulonephritis.

Piezo1 channel activates ADAM10 sheddase to regulate Notch1 and gene expression

“…Therefore Piezo1 regulation of the ADAM10/Notch1 pathway was not dependent on Yoda1. In conclusion, we connect the new discovery of Piezo1 mechanosensing with the extensive prior discoveries of the ADAM and Notch fields 1,19 . The ability of Piezo1 to activate ADAM10 and Notch1 suggests that these mechanisms are downstream of Piezo1 and therefore linked via Piezo1 to changes in physiological force.…”

“…Our findings are consistent with prior studies of D melanogaster that inferred Notch to be downstream of Piezo 29 and so the proposed mechanism may have broad relevance. Prior work showed important effects of endothelial-specific disruption of Notch1-regulated RBPJ on hepatic microvasculature 19,28 . Disruption of RBPJ in 6 week-old mice led to enlarged sinusoids between portal and central venules, and disruption earlier in postnatal development caused poor perfusion, hypoxia and liver necrosis 28 .…”

“…To test the physiological relevance, we investigated liver where functional microvascular Piezo1 channels have been detected at the adult stage 10 and where Notch1 is important for sinusoid development 19,28 . To specifically ask about endothelial biology, liver endothelial cells were acutely isolated after 2-weeks in vivo conditional Piezo1 disruption in endothelium of adult mice (Piezo1 EC ), as previously described 10 .…”

“…Piezo1 channels are Ca 2+ -permeable non-selective cationic channels, so when force causes them to open there is Ca 2+ entry, elevation of the cytosolic Ca 2+ concentration and regulation of Ca 2+ -dependent mechanisms 7,8 . Potentially relevant to such a system is Ca 2+ and Ca 2+ -calmodulin regulation of ADAM10 17,18 , a metalloprotease or sheddase that catalyses rate-limiting S2 cleavage of Notch1 prior to -secretase-mediated S3 cleavage and release of Notch1 intracellular domain (NICD), driving downstream transcription 1,19,20 . Therefore, we speculated about a potential relationship between Piezo1 and Notch1, using endothelial cells to investigate this idea because both proteins are prominent in these cells and have established functional significance in them 1,[8][9][10]12,19 .…”

“…Potentially relevant to such a system is Ca 2+ and Ca 2+ -calmodulin regulation of ADAM10 17,18 , a metalloprotease or sheddase that catalyses rate-limiting S2 cleavage of Notch1 prior to -secretase-mediated S3 cleavage and release of Notch1 intracellular domain (NICD), driving downstream transcription 1,19,20 . Therefore, we speculated about a potential relationship between Piezo1 and Notch1, using endothelial cells to investigate this idea because both proteins are prominent in these cells and have established functional significance in them 1,[8][9][10]12,19 . Because mechanical force can affect numerous mechanisms, we explored the relationship by specifically activating Piezo1 channels with a synthetic small-molecule agonist (Yoda1) that acts directly to enhance force sensitivity [21][22][23][24] .…”