(VE)-Cadherin, Endothelial Adherens Junctions, and Vascular Disease
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Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Vascular Endothelial (VE)-Cadherin, Endothelial Adherens Junctions, and Vascular Disease Maria Grazia Lampugnani,1,2 Elisabetta Dejana,1,3 and Costanza Giampietro1 1Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology, 20139 Milan, Italy 2Mario Negri Institute for Pharmacological Research, 20156 Milan, Italy 3Department of Immunology, Genetics and Pathology, Uppsala University, 75185 Uppsala, Sweden Correspondence: [email protected]; [email protected]; [email protected] Endothelial cell–cell adherens junctions (AJs) supervise fundamental vascular functions, such as the control of permeability and transmigration of circulating leukocytes, and the mainte- nance of existing vessels and formation of new ones. These processes are often dysregulated in pathologies. However, the evidence that links dysfunction of endothelial AJs to human pathologies is mostly correlative. In this review, we present an update of the molecular organization of AJ complexes in endothelial cells (ECs) that is mainly based on observations from experimental models. Furthermore, we report in detail on a human pathology, cerebral cavernous malformation (CCM), which is initiated by loss-of-function mutations in the genes that encode the three cytoplasmic components of AJs (CCM1, CCM2, and CCM3). At present, these represent a unique example of mutations in components of endothelial AJs that cause human disease. We describe also how studies into the defects of AJs in CCM are shedding light on the crucial regulatory mechanisms and signaling activities of these endothelial structures. Although these observations are specific for CCM, they support the concept that dysfunction of endothelial AJs can directly contribute to human pathologies. n the endothelium of established blood vessels, tions. The cell–cell junctions in the endothelium Icell–cell junctions connect and coordinate are defined as tight junctions and adherens the activities of the individual endothelial junctions (AJs), which are intermixed in ECs cells (ECs) for the control of vascular permeabil- (Vorbrodt and Dobrogowska 2003; Dejana ity, immune cell trafficking, and angiogenesis 2004; Vestweber et al. 2009), in contrast to their (Table 1) (Dejana and Vestweber 2013). To ac- strict apical-basal distribution in epithelial cells. complish these functions, endothelial cell–cell Tight junctions provide strict control of vessel junctions need to be structurally and function- permeability, as is required in particular for the ally dynamic (Millan et al. 2010; van Buul blood–brain barrier (Abbott et al. 2006; Banks and Timmerman 2016). Under physiological 2016; Park-Windhol and D’Amore 2016). situations, such plasticity is tightly controlled, In this review, we mainly report on the latest although should this regulation be loosened, findings relating to the structure and regulation this can cause or exacerbate pathological condi- of homotypic AJs, which are ubiquitous along Editors: Carien M. Niessen and Alpha S. Yap Additional Perspectives on Cell–Cell Junctions available at www.cshperspectives.org Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a029322 1 Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press M.G. Lampugnani et al. Table 1. Endothelial functions that require VE-cadherin Function System Activities Vessel organization – During embryogenesis: in mouse (Carmeliet et al. 1999) and zebrafish (Montero-Balaguer et al. 2009) Polarity and lumen – In vitro cultured ECs and in vivo during embryogenesis formation (Lampugnani et al. 2010) Proliferation Inhibition In vitro cultured ECs (Giampietro et al. 2012) Migration Inhibition In vitro cultured ECs and in vivo mouse models (Giampietro et al. 2012) Protection from – In vitro cultured ECs (Giampietro et al. 2012) and in vivo in mouse apoptosis embryo (Carmeliet et al. 1999) Mechanosensing – In vitro cultured ECs and in vivo in association with Pecam-1, VEGFR2, and VEGFR3. VE-cadherin does not directly transduce mechanical forces, but it is essential for downstream signaling (Tzima et al. 2005; Coon et al. 2015) Control of permeability In stabilized In vivo, in vasculature exposed to high mechanical stress (Corada vessels et al. 1999; Frye et al. 2015); not required in brain and skin (Frye et al. 2015) In response to In vivo through the Tsad/VEGFR2/Src complex (Sun et al. 2012) VEGF and Src-mediated phosphorylation of VE-cadherin Y658 In response to In vitro and in vivo through Src-mediated phosphorylation of bradykinin VE-cadherin on Y658 and Y685 (Orsenigo et al. 2012) In response to In vivo through phosphorylation of VE-cadherin Y685 (Wessel histamine et al. 2014) Control of – In vivo the stabilization of the VE-cadherin/β-catenin complex transmigration blocks leukocyte extravasation (Schulte et al. 2011). In vivo dephosphorylation of VE-cadherin on Y731 enables leukocyte diapedesis (Wessel et al. 2014) the vascular tree (for heterotypic cell–cell junc- Vascular Endothelial Cadherin: Adhesive tions between ECs and cells of either the vascu- Receptor and Signaling Mediator lar wall or the tissue stroma, see Armulik et al. 2011). We also discuss a human vascular disease Homophilic adhesion between vascular endo- in which mutations of the components of endo- thelial (VE)-cadherin molecules is crucial for thelial AJs have a causal role in the human pa- the organization of the nascent vascular net- thology. work (Carmeliet et al. 1999; Montero-Balaguer et al. 2009). Although homophilic adhesive rec- ognition between VE-cadherin molecules does ENDOTHELIAL AJs: ACTORS AND not require the VE-cadherin cytoplasmic tail INTERACTIONS (Navarro et al. 1995; Baumgartner et al. 2000), The molecular organization of endothelial AJs this domain is essential for junction stabilization has been described in detail in many previous and for tethering of an increasingly wide collec- reviews (Vestweber et al. 2009; Dejana and tion of cytoplasmic molecules that have scaffold Giampietro 2012; Giannotta et al. 2013). There- functions and/or enzymatic activities. Recruit- fore, this section focuses specifically on new ment of small GTPases and their guanine nucle- interactors and regulators of endothelial AJs otide exchange factors (GEFs) and GTPase-ac- (Fig. 1). These represent potential therapeutic tivating proteins (GAPs) is particularly crucial targets to correct barrier and angiogenesis de- here, as these define the local cortical versus fects in several pathologies, including chronic radial organization of the actin fibers, thus reg- inflammation, atherosclerosis, and tumors. ulating the plasticity of the cell–cell junctions. 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a029322 Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press A NASCENT ADHERENS JUNCTION EC5 EC4 EC3 EC2 EC1 VE-cadherin p120 TRIO β-catenin α-catenin GTP-Rac1 EPS8 Radial actin Cortical actin PI3K/Akt Increased VE-cadherin turnover Dynamic AJ Junction stabilization B STABILIZED ADHERENS JUNCTION VE-cadherin HEG1 p120 Rab11a-GTP FIP2 Increased targeting of VE-cadherin β-catenin CCM1 to membrane Rasip1 Stabilization of cell-cell contacts α Establishment of vascular integrity Stable AJ and active barrier function G 13-GTP α-catenin CCM2 14-3-3 Rap1-GTP YAP CCM3 Src activation VE-cadherin phosphorylation (Y658) and internalization AJ disassembly PI3K/Akt Rho inhibition Inactive barrier function Scaffold protein “X” Stable AJ α-catenin Active barrier function Cortical actin Stable AJ Figure 1. New interactors of endothelial adherens junctions (AJs). Recently described interactors of VE-cadherin complexes and their functions in nascent (A) and stabilized (B) endothelial AJs are represented as discussed in the text. In addition, in (A), the binding of EGF receptor kinase substrate 8 (EPS8) to the AJ complex is shown to inhibit the phosphatidylinositol-3-kinase (PI3K)/AKT (protein kinase B) pathway, thus increasing VE-cadherin turnover at AJs (Giampietro et al. 2015) and maintaining dynamic AJs. Conversely, in stabilized AJs (B), the active PI3K/AKT pathway induces phosphorylation and cytoplasmic localization of the Yes-associated protein (YAP), which localizes to junctions and contributes to enhanced barrier function. As discussed in the text and shown in B, Rasip1 is required during stabilization of cell–cell contacts, but it is not necessary for their main- tenance. The representation of the VE-cadherin domains interacting in trans (EC1-EC1) and in cis (EC1-EC2) are according to Harrison et al. (2011) and Brasch et al. (2012). Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a029322 3 Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press M.G. Lampugnani et al. The interaction of VE-cadherin with α-catenin promote opposite effects at endothelial AJs, occurs through β-catenin, which is fundamental which depend on the state of the AJs (i.e., estab- to dynamically engage the cytoskeleton (Vest- lished versus nascent) and on the type of weber et al. 2009; Dorland and Huveneers stimulus. For a comprehensive