Increased endothelial cell permeability in endoglin-deficient cells

Abstract

Endoglin (ENG) is a TGF-b superfamily coreceptor essential for vascular endothelium integrity. ENG mutations lead to a vascular dysplasia associated with frequent hemorrhages in multiple organs, whereas ENG null mouse embryos die at midgestation with impaired heart development and leaky vasculature. ENG interacts with several proteins involved in cell adhesion, and we postulated that it regulates vascular permeability. The current study assessed the permeability of ENG homozygous null (Eng 2/2 ), heterozygous (Eng +/2 ), and normal (Eng +/+ ) mouse embryonic endothelial cell (EC) lines. Permeability, measured by passage of fluorescent dextran through EC monolayers, was increased 2.9-and 1.7-fold for Eng 2/2 and Eng +/2 ECs, respectively, compared to control ECs and was not increased by TGF-b1 or VEGF. Prolonged starvation increased Eng 2/2 EC permeability by 3.7-fold with no effect on control ECs; neutrophils transmigrated faster through Eng 2/2 than Eng +/+ monolayers. Using a pull-down assay, we demonstrate that Ras homolog gene family (Rho) A is constitutively active in Eng 2/2 and EngECs. We show that the endothelial barrier destabilizing factor thrombospondin-1 and its receptor-like protein tyrosine phosphatase are increased, whereas stabilizing factors VEGF receptor 2, vascular endothelial-cadherin, p21-activated kinase, and Ras-related C3 botulinum toxin substrate 2 are decreased in Eng 2/2 cells. Our findings indicate that ENG deficiency leads to EC hyperpermeability through constitutive activation of RhoA and destabilization of endothelial barrier function.-Jerkic, M., Letarte, M. Increased endothelial cell permeability in endoglin-deficient cells. FASEB J. 29, 3678-3688 (2015). www.fasebj.org

The role of endoglin in post-ischemic revascularization

“…Recently, vascular permeability, measured by the passage of fluorescent dextran through EC monolayers, was shown to be increased in Eng -/-and Eng +/-ECs compared with control ECs. This hyperpermeability of endoglin-deficient EC monolayers is associated with a decrease in VE-cadherin expression and constitutive activation of RhoA, and it was further increased by TGF-β1 or VEGF [190]. In this context, the potential involvement of VEcadherin deserves further analysis.…”

Compartmentalized nitric oxide signaling in the resistance vasculature

“…Endoglin is part of the transforming growth factor beta (TGF-β) receptor complex; TGF-β1 leads to increased vasodilation by endoglin-dependent transcriptional increase in eNOS levels mediated by ALK5 and its downstream substrate Smad2 [50]. Recent work demonstrated that loss of endoglin in endothelial cells causes eNOS uncoupling and up-regulation of TSP-1 [51]. Because TSP-1 converts latent into active TGF-β1 as well as suppresses NO signaling, endoglin expression is critical for endothelial cell function and loss of expression may be a major contributing factor to vascular dysfunction.…”

Continuous Endoglin (CD105) Overexpression Disrupts Angiogenesis and Facilitates Tumor Cell Metastasis

“…Thus, during the final phases, it seems necessary for endoglin levels to decrease to basal levels to allow the maturation of the vessels, as sustained endoglin overexpression maintains the activation of ECs. Some authors have shown that endoglin-deficient vessels also present altered stabilization and maturation (35,39), giving rise to more permeable vessels (35,40,41). However, this phenotype seems to be explained by the lack of direct interaction between endothelial endoglin and the integrins of pericytes (35).…”