Abstract
Endoglin is a membrane glycoprotein primarily expressed by the vascular endothelium and involved in cardiovascular diseases. Upon the proteolytic processing of the membrane-bound protein, a circulating form of endoglin (soluble endoglin, sEng) can be released, and high levels of sEng have been observed in several endothelial-related pathological conditions, where it appears to contribute to endothelial dysfunction. Preeclampsia is a multisystem disorder of high prevalence in pregnant women characterized by the onset of high blood pressure and associated with increased levels of sEng. Although a pathogenic role for sEng involving hypertension has been reported in several animal models of preeclampsia, the exact molecular mechanisms implicated remain to be identified. To search for sEng-induced mediators of hypertension, we analyzed the protein secretome of human endothelial cells in the presence of sEng. We found that sEng induces the expression of BMP4 in endothelial cells, as evidenced by their proteomic signature, gene transcript levels, and BMP4 promoter activity. A mouse model of preeclampsia with high sEng plasma levels (sEng+) showed increased transcript levels of BMP4 in lungs, stomach, and duodenum, and increased circulating levels of BMP4, compared to those of control animals. In addition, after crossing female wild type with male sEng+ mice, hypertension appeared 18 days after mating, coinciding with the appearance of high plasma levels of BMP4. Also, serum levels of sEng and BMP4 were positively correlated in pregnant women with and without preeclampsia. Interestingly, sEng-induced arterial pressure elevation in sEng+ mice was abolished in the presence of the BMP4 inhibitor noggin, suggesting that BMP4 is a downstream mediator of sEng. These results provide a better understanding on the role of sEng in the physiopathology of preeclampsia and other cardiovascular diseases, where sEng levels are increased.
Highlights
IntroductionThe transforming growth factor-β (TGF-β) signaling system is well-established and includes soluble ligands, membrane receptors, and downstream Smad mediators, involved in the complex regulation of a plethora of biological processes that, among others, impact cardiovascular diseases [1,2,3,4,5]
The transforming growth factor-β (TGF-β) signaling system is well-established and includes soluble ligands, membrane receptors, and downstream Smad mediators, involved in the complex regulation of a plethora of biological processes that, among others, impact cardiovascular diseases [1,2,3,4,5].Endoglin is a membrane co-receptor of the TGF-β family that is predominantly expressed by endothelial cells and is involved in vascular development, homeostasis, repair, and disease [6,7,8]
At day 18 of pregnancy, systolic BP (SBP) was significantly higher in fWT(sEng+ ) than in fWT(WT), suggesting the existence of a sEng-induced mediator that could account for the delay between increased sEng levels and augmented SBP (Figure 6B). Compatible with this hypothesis, we found that plasma levels of BMP4 were significantly higher in fWT(sEng+ ) than in fWT(WT) mice at day 18 of pregnancy, coinciding with the increased SBP found in pregnant fWT(sEng+ )
Summary
The transforming growth factor-β (TGF-β) signaling system is well-established and includes soluble ligands, membrane receptors, and downstream Smad mediators, involved in the complex regulation of a plethora of biological processes that, among others, impact cardiovascular diseases [1,2,3,4,5]. Endoglin is a membrane co-receptor of the TGF-β family that is predominantly expressed by endothelial cells and is involved in vascular development, homeostasis, repair, and disease [6,7,8]. Endoglin is a 180-kDa homodimeric transmembrane protein that contains a large extracellular region (561 amino acids) and a short (47 amino acids) cytosolic domain [12,13]. The juxtamembrane region of the endoglin ectodomain can be proteolytically targeted by the matrix metalloprotease 14
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