Abstract
Altered pulmonary angiogenesis contributes to disrupted alveolarization, which is the main characteristic of bronchopulmonary dysplasia (BPD). Transforming growth factor β (TGFβ) plays an important role during lung vascular development, and recent studies have demonstrated that endoglin is engaged in the modulation of TGFβ downstream signalling. Although there are two different isoforms of endoglin, L- and S-endoglin, little is known about the effect of S-endoglin in developing lungs. We analysed the expression of both L- and S-endoglin in the lung vasculature and its contribution to TGFβ-activin-like kinase (ALK)-Smad signalling with respect to BPD development. Hyperoxia impaired pulmonary angiogenesis accompanied by alveolar simplification in neonatal mouse lungs. S-endoglin, phosphorylated Smad2/3 and connective tissue growth factor levels were significantly increased in hyperoxia-exposed mice, while L-endoglin, phosphor-Smad1/5 and platelet-endothelial cell adhesion molecule-1 levels were significantly decreased. Hyperoxia suppressed the tubular growth of human pulmonary microvascular endothelial cells (ECs), and the selective inhibition of ALK5 signalling restored tubular growth. These results indicate that hyperoxia alters the balance in two isoforms of endoglin towards increased S-endoglin and that S-endoglin attenuates TGFβ-ALK1-Smad1/5 signalling but stimulates TGFβ-ALK5-Smad2/3 signalling in pulmonary ECs, which may lead to impaired pulmonary angiogenesis in developing lungs.
Highlights
Altered pulmonary angiogenesis contributes to disrupted alveolarization, which is the main characteristic of bronchopulmonary dysplasia (BPD)
Pulmonary vessel staining with platelet-endothelial cell adhesion molecule (PECAM)-1 was significantly lower in the hyperoxia group than in the control group during the entire experimental period (Fig. 1B,E,F)
Hyperoxia did not modify Smad phosphorylation or vascular endothelial growth factor (VEGF), connective tissue growth factor (CTGF) or PECAM-1 production in either L-endoglin- or S-endoglin-transfected cells (Fig. 6E,F). These results indicate that L- and S-endoglin regulate pulmonary angiogenesis differentially and that these contrasting effects are mediated by activin-like kinase 1 (ALK1) or ALK5 phosphorylating their specific downstream Smad proteins
Summary
Altered pulmonary angiogenesis contributes to disrupted alveolarization, which is the main characteristic of bronchopulmonary dysplasia (BPD). Transforming growth factor β (TGFβ) plays an important role during lung vascular development, and recent studies have demonstrated that endoglin is engaged in the modulation of TGFβ downstream signalling. Hyperoxia suppressed the tubular growth of human pulmonary microvascular endothelial cells (ECs), and the selective inhibition of ALK5 signalling restored tubular growth These results indicate that hyperoxia alters the balance in two isoforms of endoglin towards increased S-endoglin and that S-endoglin attenuates TGFβ-ALK1-Smad1/5 signalling but stimulates TGFβ-ALK5-Smad2/3 signalling in pulmonary ECs, which may lead to impaired pulmonary angiogenesis in developing lungs. TGFβ-mediated signalling is initiated by binding to a TGFβ specific membrane receptor complex in ECs that contains 3 types of receptors: type I and type II serine/threonine kinase receptors and a co-receptor or TGFβ type III receptor named endoglin, known as CD105 These receptors propagate the signal to the downstream nuclear effectors, Smads, by phosphorylation[16,18,20,21,22]. 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]
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