Expression of endoglin isoforms in the myeloid lineage and their role during aging and macrophage polarization

Abstract

Endoglin plays a crucial role in pathophysiological processes such as hereditary hemorrhagic telangiectasia (HHT), preeclampsia and cancer. Endoglin expression is upregulated during the monocyte-tomacrophage transition, but little is known about its regulation and function in these immune cells. Two different alternatively spliced isoforms of endoglin have been reported, L-endoglin and S-endoglin. Although L-endoglin is the predominant variant, here, we found that there was an increased expression of the S-endoglin isoform during senescence of the myeloid lineage in human and murine models. We performed a stable isotope labelling of amino acids in cell culture (SILAC) analysis of both L-endoglin and S-endoglin transfectants in the human promonocytic cell line U937. Analysis of differentially expressed protein clusters allowed the identification of cellular activities affected during aging. S-endoglin expression led to decreased cellular proliferation and a decreased survival response to granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced apoptosis, as well as increased oxidative stress. Gene expression and functional studies suggested that there was a nonredundant role for each endoglin isoform in monocyte biology. In addition, we found that S-endoglin impairs the monocytic differentiation into the pro-inflammatory M1 phenotype and contributes to the compromised status of macrophage functions during aging.

The role of endoglin in post-ischemic revascularization

“…This result is in agreement with the reduction in monocyte function (including oxidative burst and phagocytosis) in HHT patients [242] and in mouse monocytes lacking endoglin [243]. Moreover, a different role for endoglin isoforms in the regulation of monocyte-macrophage functions has been proposed because L-endoglin overexpression promotes a pro-inflammatory M1-like macrophage phenotype, whereas S-endoglin favors the expression of anti-inflammatory M2 macrophage markers [96].…”

“…Interestingly, S-endoglin expression is induced during senescence in ECs [93][94][95] and macrophages [96]. It is interesting that post-ischemic reperfusion is impaired in senescent individuals [67].…”

S-endoglin expression is induced in hyperoxia and contributes to altered pulmonary angiogenesis in bronchopulmonary dysplasia development

“…Evidence indicates that L-endoglin, the predominant isoform in ECs, promotes EC proliferation via TGFβ-ALK1 signalling, whereas S-endoglin acts as an antagonist of L-endoglin via activation of the TGFβ-ALK5 pathway 32,33,36,37 .To date, most studies published on endoglin have focused on L-endoglin. It has been found that L-endoglin enhances ALK1-Smad1/5 signalling in ECs, leading to proliferation and migration, which are the main characteristics of the activation phase of angiogenesis 15,18,20,22,[38][39][40][41][42][43] . However, a role of S-endoglin during endothelial senescence was recently described 36,37 .…”

“…However, a role of S-endoglin during endothelial senescence was recently described 36,37 . The S-endoglin:L-endoglin ratio increases during the senescence of ECs in vitro as well as during ageing in vascularized tissues, and the switch from L-endoglin to S-endoglin affects TGFβ-mediated cell signalling towards promoting the ALK5-Smad2/3 pathway instead of the ALK1-Smad1/5 pathway 23,37,[43][44][45] .Although the role of S-endoglin in TGFβ signalling was recently addressed in mature systemic ECs, little is known about the expression and role of S-endoglin in immature pulmonary ECs and their impacts on BPD-associated dysangiogenesis. In the present study, we analysed the expression of both L-endoglin and S-endoglin in the neonatal lung vasculature and its contribution to TGFβ-ALK-Smad signalling with respect to BPD development.…”

“…However, a role of S-endoglin during endothelial senescence was recently described 36,37 . The S-endoglin:L-endoglin ratio increases during the senescence of ECs in vitro as well as during ageing in vascularized tissues, and the switch from L-endoglin to S-endoglin affects TGFβ-mediated cell signalling towards promoting the ALK5-Smad2/3 pathway instead of the ALK1-Smad1/5 pathway 23,37,[43][44][45] .…”