Ephs and Ephrins in Adult Endothelial Biology

Vreeken, Dianne; Zhang, Huayu; Zonneveld, Anton Jan van; Gils, Janine M. van

doi:10.3390/ijms21165623

Cited by 23 publications

(17 citation statements)

References 101 publications

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“…Ephrins and Ephs are membrane-bound tyrosine kinases that signal bidirectionally. This leads to forward (in the Eph-bearing cell) and reverse (in the Ephrin-bearing cell) signalling in adjacent endothelial cells ( 223 ). EphrinB2-Eph4 signalling appears to support endothelial-pericyte interactions after cerebral ischaemic injury and promote the return to a functional vasculature ( 224 ).…”

Section: Molecular Mechanisms That Disrupt Vascular Function In Viralmentioning

confidence: 99%

Endothelial Cells in Emerging Viral Infections

Hol

Haraldsen

Falk

et al. 2021

Front. Cardiovasc. Med.

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There are several reasons to consider the role of endothelial cells in COVID-19 and other emerging viral infections. First, severe cases of COVID-19 show a common breakdown of central vascular functions. Second, SARS-CoV-2 replicates in endothelial cells. Third, prior deterioration of vascular function exacerbates disease, as the most common comorbidities of COVID-19 (obesity, hypertension, and diabetes) are all associated with endothelial dysfunction. Importantly, SARS-CoV-2's ability to infect endothelium is shared by many emerging viruses, including henipaviruses, hantavirus, and highly pathogenic avian influenza virus, all specifically targeting endothelial cells. The ability to infect endothelium appears to support generalised dissemination of infection and facilitate the access to certain tissues. The disturbed vascular function observed in severe COVID-19 is also a prominent feature of many other life-threatening viral diseases, underscoring the need to understand how viruses modulate endothelial function. We here review the role of vascular endothelial cells in emerging viral infections, starting with a summary of endothelial cells as key mediators and regulators of vascular and immune responses in health and infection. Next, we discuss endotheliotropism as a possible virulence factor and detail features that regulate viruses' ability to attach to and enter endothelial cells. We move on to review how endothelial cells detect invading viruses and respond to infection, with particular focus on pathways that may influence vascular function and the host immune system. Finally, we discuss how endothelial cell function can be dysregulated in viral disease, either by viral components or as bystander victims of overshooting or detrimental inflammatory and immune responses. Many aspects of how viruses interact with the endothelium remain poorly understood. Considering the diversity of such mechanisms among different emerging viruses allows us to highlight common features that may be of general validity and point out important challenges.

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Section: Molecular Mechanisms That Disrupt Vascular Function In Viralmentioning

confidence: 99%

Endothelial Cells in Emerging Viral Infections

Hol

Haraldsen

Falk

et al. 2021

Front. Cardiovasc. Med.

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“…Importantly the ephrin-A molecules localize to lipid rafts/micro-compartments within the plasma membrane and engage transmembrane proteins, such as caveolins, neurotrophin receptor p75 and intracellular Src family kinase dependent signaling (Davy et al, 1999 ; Davy and Robbins, 2000 ; Lim et al, 2008 ). The signaling through Eph-ephrin interactions is essential for a number of developmental and pathophysiological processes (Boyd et al, 2014 ; Kania and Klein, 2016 ), including cell attachment, spreading, migration, tissue boundary formation, cellular differentiation, stem cell niche maintenance and proliferation, axon guidance, neural plasticity, somatogenesis, angiogenesis, vasculogenesis, hematopoiesis, immune cell function, cancer tumorigenicity, tissue repair, skeletal development and homeostasis (Kullander and Klein, 2002 ; Cramer and Miko, 2016 ; Kania and Klein, 2016 ; Yang et al, 2018a ; Darling and Lamb, 2019 ; Alfaro et al, 2020 ; Buckens et al, 2020 ; Fernandez-Alonso et al, 2020 ; Giorgio et al, 2020 ; Vreeken et al, 2020 ).…”

Section: Overview Of the Eph-ephrin Moleculesmentioning

confidence: 99%

“…Endothelial cells form blood vessels, supplying the skeletal tissue with nutrients, hormones, oxygen and growth factors, and are critical to skeletal growth, homeostasis and repair (Peng et al, 2020 ; Zhao and Xie, 2020 ). A recent review has highlighted the involvement of Eph-ephrin signaling in different endothelial cell populations (Vreeken et al, 2020 ), with few studies investigating the role of Eph-ephrin homotypic and heterotypic communication between mesenchymal and endothelial cells, during vascularization (formation of the vasculature), angiogenesis (expansion and remodeling of the vasculature) and capillary formation (Adams et al, 1999 ; Adams and Klein, 2000 ; Salvucci and Tosato, 2012 ). The B-subclass Eph-ephrin molecules have predominantly been implicated in these processes, where EphB4 and ephrin-B2 null mice are embryonically lethal (Wang et al, 1998 ).…”

Section: The Role Of Eph-ephrin Signaling In Vascularization and Angimentioning

confidence: 99%

Eph-Ephrin Signaling Mediates Cross-Talk Within the Bone Microenvironment

Arthur

Gronthos

2021

Front. Cell Dev. Biol.

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Skeletal integrity is maintained through the tightly regulated bone remodeling process that occurs continuously throughout postnatal life to replace old bone and to repair skeletal damage. This is maintained primarily through complex interactions between bone resorbing osteoclasts and bone forming osteoblasts. Other elements within the bone microenvironment, including stromal, osteogenic, hematopoietic, endothelial and neural cells, also contribute to maintaining skeletal integrity. Disruption of the dynamic interactions between these diverse cellular systems can lead to poor bone health and an increased susceptibility to skeletal diseases including osteopenia, osteoporosis, osteoarthritis, osteomalacia, and major fractures. Recent reports have implicated a direct role for the Eph tyrosine kinase receptors and their ephrin ligands during bone development, homeostasis and skeletal repair. These membrane-bound molecules mediate contact-dependent signaling through both the Eph receptors, termed forward signaling, and through the ephrin ligands, referred to as reverse signaling. This review will focus on Eph/ ephrin cross-talk as mediators of hematopoietic and stromal cell communication, and how these interactions contribute to blood/ bone marrow function and skeletal integrity during normal steady state or pathological conditions.

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“…NGCs consist of four protein families including Semaphorins, Netrins, Ephrins and Slits. While these guidance cues were originally found to be associated with the embryonic development of the nervous and vascular system ( 8 ), it is now clear they also play important regulatory roles in adult physiology ( 9 , 10 ). In addition, genetic variants in genes related to the axonal guidance pathway are found to be enriched in CVD and several novel genetic risk loci for CVD contain NGC genes ( 11 , 12 ).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Endothelial Plexin A4 Under Inflammatory Conditions Impairs Vascular Integrity

Vreeken

Bruikman

Stam

et al. 2021

Front. Cardiovasc. Med.

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Objective: Besides hyperlipidemia, inflammation is an important determinant in the initiation and the progression of atherosclerosis. As Neuroimmune Guidance Cues (NGCs) are emerging as regulators of atherosclerosis, we set out to investigate the expression and function of inflammation-regulated NGCs.Methods and results: NGC expression in human monocytes and endothelial cells was assessed using a publicly available RNA dataset. Next, the mRNA levels of expressed NGCs were analyzed in primary human monocytes and endothelial cells after stimulation with IL1β or TNFα. Upon stimulation a total of 14 and 19 NGCs in monocytes and endothelial cells, respectively, were differentially expressed. Since plexin A4 (PLXNA4) was strongly downregulated in endothelial cells under inflammatory conditions, the role of PLXNA4 in endothelial function was investigated. Knockdown of PLXNA4 in endothelial cells markedly impaired the integrity of the monolayer leading to more elongated cells with an inflammatory phenotype. In addition, these cells showed an increase in actin stress fibers and decreased cell-cell junctions. Functional assays revealed decreased barrier function and capillary network formation of the endothelial cells, while vascular leakage and trans-endothelial migration of monocytes was increased.Conclusion: The current study demonstrates that pro-inflammatory conditions result in differential expression of NGCs in endothelial cells and monocytes, both culprit cell types in atherosclerosis. Specifically, endothelial PLXNA4 is reduced upon inflammation, while PLXNA4 maintains endothelial barrier function thereby preventing vascular leakage of fluids as well as cells. Taken together, PLXNA4 may well have a causal role in atherogenesis that deserves further investigation.

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Ephs and Ephrins in Adult Endothelial Biology

Cited by 23 publications

References 101 publications

Endothelial Cells in Emerging Viral Infections

Endothelial Cells in Emerging Viral Infections

Eph-Ephrin Signaling Mediates Cross-Talk Within the Bone Microenvironment

Downregulation of Endothelial Plexin A4 Under Inflammatory Conditions Impairs Vascular Integrity

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