Endothelial endoglin is involved in inflammation: role in leukocyte adhesion and transmigration

Abstract

Key Points• Endothelial endoglin has a regulatory role in leukocyte trafficking through vascular endothelia.• Leukocytes and endothelial cells interact via integrin receptors and endoglin, being this cell adhesion process stimulated by inflammatory stimuli.Human endoglin is an RGD-containing transmembrane glycoprotein identified in vascular endothelial cells. Although endoglin is essential for angiogenesis and its expression is up-regulated in inflammation and at sites of leukocyte extravasation, its role in leukocyte trafficking is unknown. This function was tested in endoglin heterozygous mice (Eng ؉/؊ ) and their wild-type siblings Eng ؉/؉ treated with carrageenan or LPS as inflammatory agents. Both stimuli showed that inflammation-induced leukocyte transendothelial migration to peritoneum or lungs was significantly lower in Eng ؉/؊ than in Eng ؉/؉ mice. Leukocyte transmigration through cell monolayers of endoglin transfectants was clearly enhanced in the presence of endoglin. Coating transwells with the RGD-containing extracellular domain of endoglin, enhanced leukocyte transmigration, and this increased motility was inhibited by soluble endoglin. Leukocytes stimulated with CXCL12, a chemokine involved in inflammation, strongly adhered to endoglincoated plates and to endoglin-expressing endothelial cells. This endoglin-dependent adhesion was abolished by soluble endoglin, RGD peptides, the anti-integrin ␣5␤1 inhibitory antibody LIA1/2 and the chemokine receptor inhibitor AMD3100. These results demonstrate for the first time that endothelial endoglin interacts with leukocyte integrin ␣5␤1 via its RGD motif, and this adhesion process is stimulated by the inflammatory chemokine CXCL12, suggesting a regulatory role for endoglin in transendothelial leukocyte trafficking. (Blood. 2013;121(2):403-415) IntroductionThe vascular endothelium controls the transit of white blood cells into and out of the bloodstream. The migration of leukocytes involves the adhesive interaction of cell surface receptors with ligands expressed on endothelial cells in a process regulated by inflammatory stimuli. Stromal-derived factor 1 (SDF1␣), renamed CXCL12, is a potent chemoattractant for a variety of cells including lymphocytes, monocytes, dendritic cells, and hematopoietic stem cells. 1 CXCL12 and its receptor CXCR4 play relevant roles in immune and inflammatory responses, including leukocyte migration and recruitment, as well as integrin-dependent adhesion and transendothelial migration. 1 CXCL12 is a critical activator of endothelial progenitors by inducing a proangiogenic phenotype and increasing migration and rolling mediated by ␣4 and ␣M integrin subunits. 2 The process of leukocyte migration through the endothelial cell monolayer involves an interaction between leukocytes' integrins and endothelial-cell receptors, both acting as adhesion molecules. Integrins most relevant to leukocytes belong to the ␤ 1 -integrin and the ␤ 2 -integrin subfamilies. Classic chemoattractants and chemokines are the most powerful physiologic activat...

The role of endoglin in post-ischemic revascularization

“…In addition, a physical and functional interplay between endoglin and β1 integrins has been reported [107,196,209,234]. More recently, endothelial endoglin has been identified as a ligand for leukocyte integrins [27].…”

“…Interestingly, integrins can be activated by proangiogenic chemokines such as CXCL12, triggering EC and leukocyte spreading and migration in an integrin-dependent manner [27,[57][58][59]. Moreover, CXCL12, which is upregulated by hypoxia [60], increases PDGF-B expression by ECs and promotes the differentiation and recruitment of pericytes and vascular remodeling [61], as well as myogenic differentiation [62].…”

“…Structurally, the extracellular region of endoglin contains two distinct domains: (i) a zona pellucida (ZP) juxtamembrane domain that in human endoglin displays the prototypic Arg-Gly-Asp (RGD) motif involved in integrin-based interactions [84,85], which has a mouse homologous sequence, TDD [27]; and (ii) the NH2-terminal orphan domain involved in binding to BMP9, another member of the TGF-β family [85][86][87]. In addition to having a single transmembrane region, endoglin has a constitutively phosphorylated short intracellular domain, in which a PDZ binding domain plays a relevant role [84,88,89].…”

“…Moreover, endoglin is used as a biomarker for a poor prognosis in several cancers [23,24], and endoglin-neutralizing antibodies have demonstrated antitumor angiogenesis properties, as recently reviewed [25,26]. Additionally, a new role for endoglin in integrin-mediated angiogenic and vascular remodeling processes can be suggested in light of the recent discovery that endoglin is involved in the regulation of leukocyte recruitment [27] and in integrin-dependent cell adhesion processes, including pericyte attachment to ECs [28].…”

Expression of Cd105 and Cd31 in Benign and Malignant Salivary Gland Tumors With Myoepithelial Differentiation (A Comparative Study).

“…The immunoreactivity in non neoplastic salivary tissues may be attributed to marked upregulation of CD31 and CD105 in ECs of inflamed tissues with an associated inflammatory cell infiltrate, thus reflecting the activation of angiogenesis in tissues which may be subjected to inflammatory stimuli (Pusztaszeri et al, 2006 amd Rossi et al, 2013). From this point, the current findings can be explained by the development of angiogenic activity in non neoplastic salivary gland tissues which may be subjected to inflammatory stimuli.…”