Extreme hydrops fetalis and cardiovascular abnormalities in mice lacking a functional Adrenomedullin gene ABSTRACT Adrenomedullin(Adm), a potent 52-aa peptide vasodilator, was isolated from a human pheochromocytoma on the basis of its ability to elevate platelet CAMP levels Cl). Recently, Adm has gained much attention in clinical settings because of its elevated plasma levels in patients with various cardiovascular diseases(2). However, the variety of conditions associated with elevated Adm levels, which include essential hypertension, septic shock, and normal pregnancy, suggest that increases in Adm are secondary to other primary events rather than causative. For example, Adm may be elevated in certain hypertensive disease states as a compensatory mechanism to decrease blood pressure, but genetic experiments to distinguish between causation and compensation have not yet been performed.
On the basis of its nucleotide homologies with calcitonin gene-related peptide (CGRP), calcitonin, and amylin, Adm is considered to be the fourth CGRP family member. TheAdm gene contains four exons panning approximately 2 and codes for two biologically active peptides: oadrenomedullin N-terminal 20 peptide(PAMP) Recent studies to identify the receptors for A and CGRP have led to the discovery of a mechanism of signal transduction kb whereby a series of single transmembrane spanning receptor activity-modifying proteins(RAMPs) interact with a common receptor to impart specificity of binding for either Adm or CGRP(3). The differential expression of the receptor activity-modifying proteins may dictate the sites of function of the twe ligands.
To explore the physiological functions of Adm in an in vivo model, we used homologous recombination in embryonic stem cells to generate mice that are deficient the coding region of the Adm gene. At the same time, to provide biological marker for sites of Adm gene expression, we replaced the Adm coding region with a sequence coding for enhanced green fluorescent protein(EGFP) while leaving the Adm promoter and Adm 5' untranslated region intact. Here we show that Adm is essential for survival because Adm embryos die at midgestation with extreme hydrops fetalis. In addition, Adm embryos have unusual cardiovascular defects that are best characterized as overdeveloped ventricular trabeculae and underdeveloped vascular smooth muscle in the large arteries. Because the combination of cardiovascular defects and the severity of hydrops fetalis are, to our knowledge, unlike any previously described pathology in the mouse, our data demonstrate a unique role for A in development and suggest that the absence of Adm may be one cause of non immune hydrops fetalis in humans.