Preeclampsia is a disorder of impaired placentation. ELABELA (ELA) encodes an endogenous ligand for the apelin receptor and is detected in preimplantation human blastocysts and in 2 organs in adults: the placenta and kidney. Recently, an international team of researchers described their study findings on ELA and its role in placental vascular development and preeclampsia in mice.
Details of the study
To delineate the contribution of ELA to mammalian development, Ho and colleagues generated Ela knockout mice. The investigators showed that during development, the ELA protein is first detected in the early placenta and becomes abundant later in placenta formation. They also demonstrated that ELA is a pregnancy hormone that circulates in the blood of pregnant, but not nonpregnant, mice.
Placental structure. The Ela knockout mice had placentas that demonstrated thin labyrinths, with poor vascularization, increased apoptosis, and reduced proliferation. Further, RNA analysis of ELA-lacking placentas revealed a gene expression profile indicative of hypoxia, including the upregulation of certain genes involved in blood vessel building. Placental vessels showed overall stunted architecture characterized by little or no extension and branching of angiogenic sprouts and impaired formation of the adequate labyrinth network required for proper perfusion in the placenta.
Given these gene expression findings and the fact that placental and vascular abnormalities have long been suspected to underlie preeclampsia, the investigators sought to determine if ELA-lacking mice exhibit preeclampsia. Evidence indicated they do.
Indicators of preeclampsia. Pregnant ELA-lacking mice had significantly higher levels of proteinuria and significantly higher blood pressure than either pregnant wild-type mice or nonpregnant ELA-lacking mice. Further, at the end of pregnancy, histology and transmission electron microscopy of kidney glomerular sections from ELA-lacking pregnant mice revealed signs of endotheliosis, a unique renal pathology that is also observed in women with preeclampsia. Pups of ELA-lacking mothers tended to weigh less than those of wild-type mothers, a situation that may be similar to the fetal intrauterine growth restriction commonly seen in women with preeclampsia.
Angiogenic factors. The authors then looked at levels of angiogenic proteins implicated in the pathogenesis of preeclampsia to determine if ELA is upstream. They found that ELA-lacking mice placentas had increased levels of sFlt1, Vegfa, and Plgf mRNA; these transcriptional changes, however, did not translate into significantly elevated plasma levels of the respective proteins. Thus, these findings indicate that ELA acts independently of, and possibly earlier than, angiogenic factors in the pathogenesis of preeclampsia.
Experimental treatment. The authors further showed that infusing recombinant ELA protein could alleviate symptoms of preeclampsia in mice. Injection of ELA protein in ELA-lacking mice led to reduction of blood pressure, reversal of glomerular endotheliosis, and rescue of fetal growth restriction.
Study strengths and weaknesses
This animal study contributes compelling molecular evidence of ELA’s role in mammalian placental development and angiogenesis, revealing that ELA deficiency leads to preeclampsia and placental abnormalities in pregnant mice. How ELA acts in humans and human pregnancy, however, has yet to be explored.
-- Sarosh Rana, MD, MPH
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