VE-cadherin is a component of endothelial cell-to-cell adherens junctions, and it has a key role in the maintenance of vascular integrity. During embryo development, VE-cadherin is required for the organization of a stable vascular system, and in the adult it controls vascular permeability and inhibits unrestrained vascular growth. The mechanisms of action of VE-cadherin are complex and include reshaping and organization of the endothelial cell cytoskeleton and modulation of gene transcription. Here we review some of the most important pathways through which VE-cadherin modulates vascular homeostasis and discuss the emerging concepts in the overall biological role of this protein.

No abstract

A fundamental property of cellular processes is to maintain homeostasis despite varying internal and external conditions. Within the membrane transport apparatus, variations in membrane fluxes from the endoplasmic reticulum (ER) to the Golgi complex are balanced by opposite fluxes from the Golgi to the ER to maintain homeostasis between the two organelles. Here we describe a molecular device that balances transport fluxes by integrating transduction cascades with the transport machinery. Specifically, ER-to-Golgi transport activates the KDEL receptor at the Golgi, which triggers a cascade that involves Gs and adenylyl cyclase and phosphodiesterase isoforms and then PKA activation and results in the phosphorylation of transport machinery proteins. This induces retrograde traffic to the ER and balances transport fluxes between the ER and Golgi. Moreover, the KDEL receptor activates CREB1 and other transcription factors that upregulate transport-related genes. Thus, a Golgi-based control system maintains transport homeostasis through both signaling and transcriptional networks.

Membrane trafficking involves large fluxes of cargo and membrane across separate compartments. These fluxes must be regulated by control systems to maintain homoeostasis. While control systems for other key functions such as protein folding or the cell cycle are well known, the mechanisms that control secretory transport are poorly understood. We have previously described a signalling circuit operating at the Golgi complex that regulates intra‐Golgi trafficking and is initiated by the KDEL receptor (KDEL‐R), a protein previously known to mediate protein recycling from the Golgi to the endoplasmic reticulum (ER). Here, we investigated the KDEL‐R signalling mechanism. We show that the KDEL‐R is predicted to fold like a G‐protein‐coupled receptor (GPCR), and that it binds and activates the heterotrimeric signalling G‐protein Gαq/11 which, in turn, regulates transport through the Golgi complex. These findings reveal an unexpected GPCR‐like mode of action of the KDEL‐R and shed light on a core molecular control mechanism of intra‐Golgi traffic.

Cerebral cavernous malformation (CCM) is a neurovascular familial or sporadic disease that is characterised by capillary-venous cavernomas, and is due to loss-of-function mutations to any one of three CCM genes. Familial CCM follows a two-hit mechanism similar to that of tumour suppressor genes, while in sporadic cavernomas only a small fraction of endothelial cells shows mutated CCM genes. We reported that in mouse models and in human patients, endothelial cells lining the lesions have different features from the surrounding endothelium, as they express mesenchymal/stem-cell markers. Here we show that cavernomas originate from clonal expansion of few Ccm3 -null endothelial cells that express mesenchymal/stem-cell markers. These cells then attract surrounding wild-type endothelial cells, inducing them to express mesenchymal/stem-cell markers and to contribute to cavernoma growth. These characteristics of Ccm3 -null cells are reminiscent of the tumour-initiating cells that are responsible for tumour growth. Our data support the concept that CCM has benign tumour characteristics.