Potential Role of Circulating Endoglin in Hypertension via the Upregulated Expression of BMP4

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.

Pregnancy-Induced High Plasma Levels of Soluble Endoglin in Mice Lead to Preeclampsia Symptoms and Placental Abnormalities

“…The presence of high circulating levels of sEng in preeclampsia has been widely described, and therefore it has been proposed as an early diagnostic and prognostic biomarker of this disease [ 18 , 44 , 45 ]. Moreover, several studies in animal models have demonstrated that increased plasma levels of sEng could play a pathogenic role in preeclampsia [ 14 , 18 , 24 , 26 ]. However, the animal models used up to date might not be wholly representative of the actual disease, as the symptoms associated with increased plasma levels of sEng in those models were not dependent on gestation, and only phenocopied the so-called second step of the disease, related to the systemic mother’s response and associated clinical symptoms [ 46 ].…”

“…Moreover, our results suggest that the contribution of high levels of sEng to the preeclampsia phenotype is not immediate but needs a sustained increase of plasma sEng. Interestingly, we recently described that sEng induced the expression of BMP4 which, in turn, mediated the sEng-dependent effect in hypertension [ 26 ]. The existence of this intermediate may account for the observed delay between the appearance of increased plasma sEng levels and an increase in blood pressure.…”

“…Of note, expression levels and enzymatic activity of MMP-14 are increased in various conditions related to endothelial injury, activation, inflammation and senescence, as well as in pregnancy [ 17 , 18 , 19 , 20 , 21 ]. Several lines of evidence support a functional role of sEng in cardiovascular conditions and diseases, including endothelial dysfunction, anti-angiogenic activity, hypertension, increased vascular permeability, vascular remodeling, and inflammation-associated leukocyte adhesion and extravasation [ 8 , 14 , 20 , 22 , 23 , 24 , 25 , 26 , 27 ]…”

“…In this regard, we previously reported that mice continuously exposed to high circulating levels of sEng showed preeclampsia-like symptoms such as hypertension and proteinuria in the absence of pregnancy [ 14 ]. In addition, we postulated that the sEng-induced effect in hypertension was mediated by an upregulation of bone morphogenetic protein 4 (BMP4) [ 26 ]. Unfortunately, none of these studies phenocopied the maternal syndrome of preeclampsia, since they were not performed in mice with pregnancy-induced high circulating levels of sEng.…”

Cells in Cardiovascular Disease: Using Diversity to Confront Adversity

“…Another cell surface receptor that yields a soluble form involved in cardiovascular pathophysiology is endoglin, a glycoprotein primarily expressed by the vascular endothelial cells. Gallardo Vara et al study the relationship of soluble endoglin (sEng) with hypertension in preeclampsia, and using a combination of cellular and animal models find BMP4 as a downstream mediator of sEng effects [ 12 ]. Once again, these results show that circulating forms from proteolytically processed membrane-bound proteins are common in cardiovascular pathology, and can be useful as biomarkers to monitor the activation of key pathophysiological pathways involved in disease progression [ 13 ].…”