Soluble endoglin (sEng) joins the soluble fms-like tyrosine kinase (sFlt) receptor as a pre-eclampsia molecule.

Pre-eclampsia is a devastating disease of late (after week 20) pregnancy. The condition features hypertension, proteinuria, premature labor, haemolysis, liver abnormalities, thrombocytopenia (HELLP syndrome), seizures (eclampsia) and death [1]. Both mothers and children, if they survive delivery, can expect subsequent increased cardiovascular risk in the future. Preeclampsia affects about 5% of the pregnancies in affluent societies; in the rest of the world, the incidence is higher. Suffice it to say, pre-eclampsia is a major world health problem. The group led by Anand Karumanchi et al. [2] has made major contributions in terms of our understanding pre-eclampsia. They showed that preeclampsia is associated with a circulating aberrant splice variant of the vascular endothelial growth factor (VEGF) receptor fms-like tyrosine kinase (Flt). This receptor is also an important target for placental growth factor (PLGF). The soluble fms-like tryrosine kinase (sFlt) receptor is a splice variant of the VEGF receptor Flt. The Karumanchi group showed that patients with pre-eclampsia have increased circulating levels of sFlt that putatively catches VEGF and PLGF before these mediators can interact with their ligands (Figure 1, panel A). As a result, endothelial and, particularly, placental (trophoblast) growth could be stunted, causing pre-eclamspia. The hypothesis was underscored by in vitro and in vivo experiments. Serum from preeclampstic patients inhibited tube formation by endothelial cells in culture. Giving sFlt to rats caused hypertension, proteinuria and glomerular endotheliosis. Subsequently, the group collaborated with clinical investigators who had performed a randomized trial of calcium supplementation in women at risk for preeclampsia. The calcium story was negative; however, the women developing pre-eclampsia in these studies had increased circulating sFlt levels and decreased PLGF and VEGF concentrations [3]. The data appeared convincing [4]. Now, the Karumanchi group implicates an additional molecule in pre-eclampsia, namely endoglin (Eng) or CD105 [5]. The ENG gene encodes for the Eng protein. Mutations in ENG cause hereditary haemorrhagic telangiectasia Osler Rendu Weber Syndrome type 1 (HHT1), an autosomal-dominant disorder characterized by arteriovenous malformations and focal loss of capillaries. Eng is a proliferationassociated and hypoxia-inducible protein abundantly expressed in angiogenic endothelial cells. Eng is a receptor for transforming growth factor (TGF)-b1 and -b3. The protein modulates TGF-b signalling by interacting with TGF-b receptors I and II. Eng is strongly expressed in blood vessels and has become a target for cancer researchers [6]. As a result, Eng has been labelled as a tumour therapy target [7]. Eng localizes to caveolae, where the molecule associates with nitric oxide synthase [8]. Here, various mechanisms join together to assure vascular function and integrity. The Karumanchi group now reports a soluble form of Eng (sEng), analogous to sFlt, is present in the sera of pregnant women. sEng is said to be elevated in pre-eclamptic women and cooperates with sFlt to induce endothelial dysfunction in vitro and pre-eclampsia in vivo. The findings implicate TGF-b1 signalling and nitric oxide-related mechanisms in the pre-eclampsia syndrome. The investigators used an Affymetrix microarray chip and studied pre-eclampstic and normal placentas. They found that pre-eclampstic placentas overexpressed sFlt and also ENG mRNA. They confirmed this result by northern blotting and immunostaining *Comment on Venkatesha S, Toporsian M, Lam C et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 2006; 12: 642–649. Correspondence and offprint requests to: Friedrich C. Luft, Franz Volhard Clinic, Medical Faculty of the Charité, HELIOS Klinikum-Berlin, Max Delbrück Center for Molecular Medicine, Berlin Buch, Wiltberg Strasse 50, 13125 Berlin, Germany. Email: [email protected] Nephrol Dial Transplant (2006) 21: 3052–3054