Migration of leukocytes into tissue is a key element of innate and adaptive immunity. While the capturing of leukocytes to the blood vessel wall is well understood, little is known about the ...mechanisms underlying the actual transmigration of leukocytes through the vessel wall (diapedesis). Even a basic question such as whether leukocytes migrate through openings between adjacent endothelial cells (junctional pathway) or through single endothelial cells (transcellular pathway) is still a matter of intensive debate. It is generally accepted that both pathways exist; however, whether they are of equal physiological significance is unclear. Several endothelial adhesion and signaling molecules have been identified, most of them at endothelial cell contacts, which participate in leukocyte diapedesis. A concept is evolving suggesting that transendothelial migration of leukocytes is a stepwise process. Blocking or eliminating some of the different adhesion and signaling proteins results in very different effects, such as trapping of leukocytes above endothelial cell contacts, in between endothelial cells, or between the endothelium and the underlying basement membrane. Other proteins are involved in the opening of endothelial cell contacts and yet others in their maintenance providing the barrier for extravasating leukocytes. The various molecular players and the functional steps involved in diapedesis are discussed.
Inflammation and immune surveillance rely on the ability of leukocytes to leave the blood stream and enter tissue. Cytokines and chemokines regulate expression and the activation state of adhesion ...molecules that enable leukocytes to adhere and arrest at sites of leukocyte exit. Capturing and arrest is followed by the transmigration of leukocytes through the vessel wall—a process called diapedesis. The review will focus on recently published novel approaches to determine the route that leukocytes take in vivo when they migrate through the endothelial layer of blood vessels. This work has revealed the dominant importance of the junctional pathway between endothelial cells in vivo. In addition, recent progress has improved our understanding of the molecular mechanisms that regulate junctional stability, the opening of endothelial junctions during leukocyte extravasation, and the induction of vascular permeability.
Endothelial junctions provide blood and lymph vessel integrity and are essential for the formation of a vascular system. They control the extravasation of solutes, leukocytes and metastatic cells ...from blood vessels and the uptake of fluid and leukocytes into the lymphatic vascular system. A multitude of adhesion molecules mediate and control the integrity and permeability of endothelial junctions. VE-cadherin is arguably the most important adhesion molecule for the formation of vascular structures, and the stability of their junctions. Interestingly, despite this prominence, its elimination from junctions in the adult organism has different consequences in the vasculature of different organs, both for blood and lymph vessels. In addition, even in tissues where the lack of VE-cadherin leads to strong plasma leaks from venules, the physical integrity of endothelial junctions is preserved. Obviously, other adhesion molecules can compensate for a loss of VE-cadherin and this review will discuss which other adhesive mechanisms contribute to the stability and regulation of endothelial junctions and cooperate with VE-cadherin in intact vessels. In addition to adhesion molecules, endothelial receptors will be discussed, which stimulate signaling processes that provide junction stability by modulating the actomyosin system, which reinforces tension of circumferential actin and dampens pulling forces of radial stress fibers. Finally, we will highlight most recent reports about the formation and control of the specialized button-like junctions of initial lymphatics, which represent the entry sites for fluid and cells into the lymphatic vascular system.
Cadherins are homophilic cell adhesion molecules that determine tissue architecture and control cell contact formation and dissociation in development and tissue homeostasis of all metazoans. These ...adhesion molecules mediate homophilic interactions between cells and are linked inside the cell via a complex set of cytosolic factors to the actin cytoskeleton. These interactions are key to the plasticity of intercellular junctions and to the various signaling functions of the cadherins. This forms the basis for cadherin-driven cell behavior, cell differentiation, and regeneration of tissue structures. Consequently, mutations in cadherins are the cause of various human pathologies, with cancer representing one of the most prominent examples.
VE-cadherin is an endothelial-specific cadherin that is essential for the formation and regulation of endothelial cell junctions. The adhesive function and expression levels of VE-cadherin at ...endothelial contacts are central determinants of the control of vascular permeability and leukocyte recruitment into tissue. In addition to controlling junctional integrity, VE-cadherin modulates a multitude of signaling processes that influence the behavior of endothelial cells, such as proliferation, survival, migration, polarity, expression of other junctional components, and tube and lumen formation of blood vessels. This chapter highlights recent progress in understanding how VE-cadherin modulates these various cellular processes. In addition, the current knowledge about how VE-cadhern participates in the regulation of the endothelial barrier in the adult organism is discussed.
Immune responses depend on the ability of leukocytes to move from the circulation into tissue. This is enabled by mechanisms that guide leukocytes to the right exit sites and allow them to cross the ...barrier of the blood vessel wall. This process is regulated by a concerted action between endothelial cells and leukocytes, whereby endothelial cells activate leukocytes and direct them to extravasation sites, and leukocytes in turn instruct endothelial cells to open a path for transmigration. This Review focuses on recently described mechanisms that control and open exit routes for leukocytes through the endothelial barrier.
A unifying concept in vascular health and disease Schwartz, Martin A; Vestweber, Dietmar; Simons, Michael
Science (American Association for the Advancement of Science),
2018-Apr-20, 2018-04-20, 20180420, Letnik:
360, Številka:
6386
Journal Article
Recenzirano
Odprti dostop
Interventions to restore blood vessel stability could improve health outcomes
Not unlike Tolstoy's remark about happy versus unhappy families, current wisdom in vascular biology holds that healthy ...blood vessels are mostly similar, whereas vessels in different vascular diseases are mostly different. But is this really the case? An evaluation of the literature suggests that unresolved vascular remodeling may be a key element of virtually all vascular diseases. This commonality raises the possibility of unifying principles that govern vascular remodeling and the possibility that methods to restore normal remodeling could effectively treat multiple disease states.
In acute neuroinflammatory states such as meningitis, neutrophils cross the blood-brain barrier (BBB) and contribute to pathological alterations of cerebral function. The mechanisms that govern ...neutrophil migration across the BBB are ill defined. Using live-cell imaging, we show that LPS-stimulated BBB endothelium supports neutrophil arrest, crawling, and diapedesis under physiological flow in vitro. Investigating the interactions of neutrophils from wild-type, CD11a(-/-), CD11b(-/-), and CD18(null) mice with wild-type, junctional adhesion molecule-A(-/-), ICAM-1(null), ICAM-2(-/-), or ICAM-1(null)/ICAM-2(-/-) primary mouse brain microvascular endothelial cells, we demonstrate that neutrophil arrest, polarization, and crawling required G-protein-coupled receptor-dependent activation of β2 integrins and binding to endothelial ICAM-1. LFA-1 was the prevailing ligand for endothelial ICAM-1 in mediating neutrophil shear resistant arrest, whereas Mac-1 was dominant over LFA-1 in mediating neutrophil polarization on the BBB in vitro. Neutrophil crawling was mediated by endothelial ICAM-1 and ICAM-2 and neutrophil LFA-1 and Mac-1. In the absence of crawling, few neutrophils maintained adhesive interactions with the BBB endothelium by remaining either stationary on endothelial junctions or displaying transient adhesive interactions characterized by a fast displacement on the endothelium along the direction of flow. Diapedesis of stationary neutrophils was unchanged by the lack of endothelial ICAM-1 and ICAM-2 and occurred exclusively via the paracellular pathway. Crawling neutrophils, although preferentially crossing the BBB through the endothelial junctions, could additionally breach the BBB via the transcellular route. Thus, β2 integrin-mediated neutrophil crawling on endothelial ICAM-1 and ICAM-2 is a prerequisite for transcellular neutrophil diapedesis across the inflamed BBB.
Edema stemming from leaky blood vessels is common in eye diseases such as age-related macular degeneration and diabetic retinopathy. Whereas therapies targeting vascular endothelial growth factor A ...(VEGFA) can suppress leakage, side-effects include vascular rarefaction and geographic atrophy. By challenging mouse models representing different steps in VEGFA/VEGF receptor 2 (VEGFR2)-induced vascular permeability, we show that targeting signaling downstream of VEGFR2 pY949 limits vascular permeability in retinopathy induced by high oxygen or by laser-wounding. Although suppressed permeability is accompanied by reduced pathological neoangiogenesis in oxygen-induced retinopathy, similarly sized lesions leak less in mutant mice, separating regulation of permeability from angiogenesis. Strikingly, vascular endothelial (VE)-cadherin phosphorylation at the Y685, but not Y658, residue is reduced when VEGFR2 pY949 signaling is impaired. These findings support a mechanism whereby VE-cadherin Y685 phosphorylation is selectively associated with excessive vascular leakage. Therapeutically, targeting VEGFR2-regulated VE-cadherin phosphorylation could suppress edema while leaving other VEGFR2-dependent functions intact.
Blood vascular endothelial cells (BECs) control the immune response by regulating blood flow and immune cell recruitment in lymphoid tissues. However, the diversity of BEC and their origins during ...immune angiogenesis remain unclear. Here we profile transcriptomes of BEC from peripheral lymph nodes and map phenotypes to the vasculature. We identify multiple subsets, including a medullary venous population whose gene signature predicts a selective role in myeloid cell (vs lymphocyte) recruitment to the medulla, confirmed by videomicroscopy. We define five capillary subsets, including a capillary resident precursor (CRP) that displays stem cell and migratory gene signatures, and contributes to homeostatic BEC turnover and to neogenesis of high endothelium after immunization. Cell alignments show retention of developmental programs along trajectories from CRP to mature venous and arterial populations. Our single cell atlas provides a molecular roadmap of the lymph node blood vasculature and defines subset specialization for leukocyte recruitment and vascular homeostasis.
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