Oxysterol-Induced Soluble Endoglin Release and Its Involvement in Hypertension

Abstract

Background-Ischemia in the placenta is considered the base of the pathogenesis of preeclampsia, a pregnancy-specific syndrome in which soluble endoglin (sEng) is a prognostic marker and plays a pathogenic role. Here, we investigated the effects of hypoxia and the downstream pathways in the release of sEng. Methods and Results-Under hypoxic conditions, the trophoblast-like cell line JAR showed an increase in sEng parallel to an elevated formation of reactive oxygen species. Because reactive oxygen species are related to the formation of oxysterols, we assessed the effect of 22-(R)-hydroxycholesterol, a natural ligand of the liver X receptor (LXR), and the LXR synthetic agonist T0901317. Treatment of JAR cells or human placental explants with 22-(R)-hydroxycholesterol or T0901317 resulted in a clear increase in sEng that was dependent on LXR. These LXR agonists induced an increased matrix metalloproteinase-14 expression and activity and a significant reduction of its endogenous inhibitor, tissue inhibitor of metalloproteinase-3. In addition, mice treated with LXR agonists underwent an increase in the plasma sEng levels, concomitant with an increase in arterial pressure. Moreover, transgenic mice overexpressing sEng displayed high blood pressure. Finally, administration of an endoglin peptide containing the consensus matrix metalloproteinase-14 cleavage site G-L prevented the oxysterol-dependent increase in arterial pressure and sEng levels in mice. Conclusions-These studies provide a clue to the involvement of the LXR pathway in sEng release and its pathogenic role in vascular disorders such as preeclampsia. (Circulation. 2012;126:2612-2624.)Key Words: cell hypoxia Ⅲ hypertension Ⅲ pre-eclampsia Ⅲ pregnancy Ⅲ peptides P reeclampsia is a pregnancy-specific syndrome characterized by systemic hypertension, proteinuria, and edema in the third trimester of pregnancy. 1,2 It affects both the fetus and the mother and occurs in Ϸ5% of pregnancies. Severe preeclampsia leads to the appearance of the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), seizures, or fetal growth restriction and can result in fetal death. Preeclampsia is thought to be the consequence of impaired placentation resulting from inadequate trophoblastic invasion of the maternal spiral arteries. 3 Abnormal placentation is an important predisposing factor for preeclampsia, whereas endothelial dysfunction appears to be central to the pathophysiological changes, possibly indicative of a 2-stage disorder characterized by reduced placental perfusion and a maternal syndrome. Hypoxia, followed by oxidative stress, has been postulated as a critical signal that initiates the pathogenic process in preeclampsia. 4,5 Hypoxia and extracellular inflammatory signals can induce the intracellular accumulation of reactive oxygen species (ROS). 6,7 In turn, the imbalance between ROS production and antioxidant systems induces oxidative stress that negatively affects reproductive processes, including cyclic luteal and endometrial changes, follicular d...

High Levels of Soluble Endoglin Induce a Proinflammatory and Oxidative-Stress Phenotype Associated with Preserved NO-Dependent Vasodilatation in Aortas from Mice Fed a High-Fat Diet

“…In addition, the purpose of this model in this study was to evaluate the effects of high levels of sEng in the mice aorta. The first paper demonstrating a functionality of this model was by Valbuena-Diez et al [11] in 2012; the authors demonstrated that mice with high levels of human sEng suffer from many of the symptoms of preeclampsia, such as hypertension, renal damage and proteinuria. …”

“…Transgenic mice overexpressing Sol-Eng + on the CBAxC57BL/ 6J background were generated at the Genetically Modified Organisms Generation Unit (University of Salamanca, Spain), as previously described [11]. Six-month-old female (n = 5) and male (n = 6) mice showing high plasma concentrations of sEng ( Sol-Eng + high ) were fed a high-fat rodent diet containing 1.25% cholesterol and 40% fat (Research Diets, Inc., N.J., USA) for the following 3 months.…”

“…Sol-Eng + mice have high levels of sEng in the blood and exhibit a preeclampsia-like phenotype, including hypertension, small pup size, proteinuria and renal damage. This is a potentially useful model to study the development of endothelial dysfunction [11]. However, recent work in our laboratory failed to demonstrate that the elevated plasma concentrations of sEng in these mice were associated with endothelial dysfunction in aorta, at either a functional or morphological level [12].…”

The role of endoglin in post-ischemic revascularization

“…A soluble form of endoglin, sEng, is released upon metalloprotease cleavage of any of the membrane isoforms [98,99]. Increased sEng shedding has been reported to play a role in vascular pathologies such as pulmonary hypertension and preeclampsia [100,101] and in several cancers [102].…”

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

“…Endoglin expression and function has been widely described in the context of endothelial cells and vascular physiology López-Novoa and Bernabeu, 2010), playing a key role in many pathological processes, including hereditary hemorrhagic telangiectasia (HHT), cancer angiogenesis, preeclampsia or hypertension (Bernabeu et al, 2009;Shovlin, 2010;Kapur et al, 2012;Rana et al, 2012;Valbuena-Diez et al, 2012). In addition, increased levels of the membrane and soluble forms of endoglin have been linked to inflammatory processes, such as wound healing, atherosclerosis, psoriasis and rheumatoid arthritis (Rulo et al, 1995;Conley et al, 2000;Torsney et al, 2002;López-Novoa and Bernabeu, 2010).…”